X-67721909-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3B:2

Conservation

PhyloP100: 6.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16319424).

BS2

High Hemizygotes in GnomAd4 at 39 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.2395C>G	p.Gln799Glu	missense_variant	Exon 6 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3 link	c.799C>G	p.Gln267Glu	missense_variant	Exon 7 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 link	c.2395C>G	p.Gln799Glu	missense_variant	Exon 6 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

144

AN:

111074

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

33258

show subpopulations

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

GnomAD3 exomes

AF:

0.00140

AC:

256

AN:

183191

Hom.:

AF XY:

0.00127

AC XY:

AN XY:

67727

show subpopulations

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 SAS exome

AF:

0.0000524

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.:

Cov.:

AF XY:

0.00146

AC XY:

532

AN XY:

363431

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00129

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00294

Gnomad4 NFE exome

AF:

0.00172

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00130

AC:

144

AN:

111074

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

33258

show subpopulations

Gnomad4 AFR

AF:

0.000230

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00151

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00352

Gnomad4 NFE

AF:

0.00211

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00167

AC:

203

EpiCase

AF:

0.00125

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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; JâˆšÂ§âˆšÂ§skelâˆšÂ§inen_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; JâˆšÂ§âˆšÂ§skelâˆšÂ§inen_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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2024	AR: BS2 -

Partial androgen insensitivity syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Malignant tumor of prostate

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 12, 2023

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. -

Male infertility

Uncertain:1

Uncertain significance, criteria provided, single submitter

in vitro;research

Institute of Reproductive Genetics, University of Münster

Jan 16, 2024

- -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Pathogenic

0.98

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

.;N;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.022

.;D;D

Sift4G

Uncertain

0.050

T;D;D

Vest4

0.88

MVP

1.0

MPC

1.2

ClinPred

0.48

GERP RS

4.8

Varity_R

0.92

gMVP

0.89

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over