X-67721909-C-G

Variant names:

• chrX-67721909-C-G
• rs137852591
• NM_000044.6:c.2395C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_000044.6(AR):​c.2395C>G​(p.Gln799Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00149 in 1,209,115 control chromosomes in the GnomAD database, including 2 homozygotes. There are 571 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 39 hem., cov: 22)
  • Exomes 𝑓: 0.0015 (2 hom. 532 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:3
• Conservation: PhyloP100: 6.17
• Publications: 26 publications found

Genes affected

AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000044.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16319424).
• BS2: High Hemizygotes in GnomAd4 at 39 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.2395C>G	p.Gln799Glu	missense	Exon 6 of 8	NP_000035.2
	AR	NM_001011645.3		c.799C>G	p.Gln267Glu	missense	Exon 7 of 9	NP_001011645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.2395C>G	p.Gln799Glu	missense	Exon 6 of 8	ENSP00000363822.3
	AR	ENST00000396043.4	TSL:1	n.*743C>G		non_coding_transcript_exon	Exon 7 of 9	ENSP00000379358.4
	AR	ENST00000396043.4	TSL:1	n.*743C>G		3_prime_UTR	Exon 7 of 9	ENSP00000379358.4

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 144 AN: 111074 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00140 AC: 256 AN: 183191 AF XY: 0.00127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.00151 AC: 1659 AN: 1098041 Hom.: 2 Cov.: 31 AF XY: 0.00146 AC XY: 532 AN XY: 363431

African (AFR) AF: 0.0000758 AC: 2 AN: 26400

American (AMR) AF: 0.000256 AC: 9 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 25 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00294 AC: 119 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00172 AC: 1452 AN: 841974

Other (OTH) AF: 0.00113 AC: 52 AN: 46089

GnomAD4 genome AF: 0.00130 AC: 144 AN: 111074 Hom.: 0 Cov.: 22 AF XY: 0.00117 AC XY: 39 AN XY: 33258

African (AFR) AF: 0.000230 AC: 7 AN: 30486

American (AMR) AF: 0.00 AC: 0 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2575

European-Finnish (FIN) AF: 0.00352 AC: 21 AN: 5970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00211 AC: 112 AN: 52975

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00167 Hom.: 40

Bravo AF: 0.000929

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00167 AC: 203

EpiCase AF: 0.00125

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AR: BS2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AR p.Q799E variant was identified in the literature in multiple patients with androgen insensitivity syndrome (AIS), including the complete, partial and mild forms (Batch_1992_PMID:1307250; Petroli_2017_PMID:29237170; Jääskeläinen_2006_PMID:16595706; Hughes_2012_PMID:23044881). The p.Q799E variant was also identified in a male azoospermic patient and a male with prostate cancer (Wang_1998_PMID:9851768; Evans_1996_PMID:8628719). The variant was identified in dbSNP (ID: rs137852591), LOVD 3.0, Cosmic and ClinVar (classified as likely pathogenic by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was also found in the Cambridge AR Mutation Database in association with mild AIS and partial AIS (Hughes_2012_PMID:23044881). The variant was identified in control databases in 305 of 204870 chromosomes (104 hemizygous) at a frequency of 0.001489 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 51 of 18607 chromosomes (freq: 0.002741), European (non-Finnish) in 229 of 92423 chromosomes (freq: 0.002478), Ashkenazi Jewish in 11 of 7652 chromosomes (freq: 0.001438), Other in 6 of 5319 chromosomes (freq: 0.001128), Latino in 6 of 28040 chromosomes (freq: 0.000214), African in 1 of 18937 chromosomes (freq: 0.000053) and South Asian in 1 of 19071 chromosomes (freq: 0.000052), but was not observed in the East Asian population. The p.Q799E variant was identiifed in combination with a p.C807F variant in a female with complete AIS; functional studies of these variant indicated that the p.Q799E variant was not harmful on its own but had a synergistic negative effect when found as a double mutant with the p.C807F variant (Petroli_2017_PMID:29237170). Petroli et al. (2017) also identified the p.Q799E variant as a double mutant with p.F726V in another patient with AIS, suggesting that the p.Q799E variant may modulate or contribute to the AIS phenotype. Despite being found in the ligand binding domain, multiple functional studies have not found any ligand binding defects from this variant, and the effect of this variant on receptor trans-activation function has been minimal or insignificant compared to wildtype (Wang_1998_PMID:9851768; Bevan_1995_PMID:8824883; Jääskeläinen_2006_PMID:16595706). The p.Gln799 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is classified as a variant of uncertain significance, although this variant may contribute to AIS when found in combination with other AR variants.

Feb 02, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two unrelated males with partial androgen insensitivity (PAIS) and has subsequently been reported in several males with idiopathic infertility who did not have other symptoms of AIS (PMID: 1307250, 7671849, 9851768, 10946887, 17054461, 32155011); Functional studies indicate that this variant does not impair androgen binding but may partially impair transactivation activity (PMID: 10946887, 1307250, 9851768); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36964972, 35809576, 36394509, 34493867, 7671849, 17054461, 28146470, 20410220, 22412043, 23637914, 8824883, 9851768, 29237170, 29723568, 29768628, 30665703, 23518348, 22645304, 22403669, 34426522, 31871297, 31980526, 32155011, 31499074, 34308104, 36459502, 36806291, 33750429, 36921044, 1307250, 10946887)

not specified Uncertain:1 Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AR c.2395C>G (p.Gln799Glu) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 183191 control chromosomes to include both hemizygous males and heterozygous females. This frequency does not allow conclusions about variant significance, although pointing to a benign outcome. c.2395C>G has been reported in the literature in settings of females with partial androgen insensitivity (example, Batch_1992), in combination with a different AR gene variant p.Cys807Phe in a female with complete androgen insensitivity (example, Petroli_2017) and in other settings such as azoospermic/infertile males (example, Wang_1998, Hiort_2000). These data do not allow any conclusion about variant significance. Multiple publications report experimental evidence evaluating an impact on protein function (example, Wang_1998, Petroli_2017). The most pronounced variant effect results in normal ability to bind androgen receptor (Wang_1998, Petroli_2017) and conflicting results in transactivation activity ranging from a slight reduction to normal levels (Wang_1998, Petroli_2017). Furthermore, a recent report has identified that a complex allele combination of this variant with p.Cys807Phe results in a deleterious outcome thereby questioning the role of this variant in isolation in the associated pathophysiology of disease (Petroli_2017). The following publications have been ascertained in the context of this evaluation (PMID: 1307250, 10946887, 29237170, 9921903). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Partial androgen insensitivity syndrome Pathogenic:1

Dec 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Prostate cancer Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Male infertility Uncertain:1

Jan 16, 2024

Institute of Reproductive Genetics, University of Münster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	0.98	D
PhyloP100		6.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.050	T
Vest4		0.88
MVP		1.0
MPC		1.2
ClinPred		0.48	T
GERP RS		4.8
Varity_R		0.92
gMVP		0.89
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852591; hg19: chrX-66941751;