X-67546320-C-T

Variant names:

• chrX-67546320-C-T
• rs201934623
• NM_000044.6:c.1174C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1 PM5 PP2 BP4_Strong BP6 BS1 BS2

The NM_000044.6(AR):​c.1174C>T​(p.Pro392Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,197,127 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,564 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P392R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 101 hem., cov: 24)
  • Exomes 𝑓: 0.0033 (15 hom. 1463 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:11
• Conservation: PhyloP100: 1.64
• Publications: 20 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: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000044.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-67546321-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1685534.
• 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=0.0062516034).
• BP6: Variant X-67546320-C-T is Benign according to our data. Variant chrX-67546320-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216890.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00231 (260/112625) while in subpopulation SAS AF = 0.0278 (76/2738). AF 95% confidence interval is 0.0227. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 101 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1174C>T	p.Pro392Ser	missense_variant	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1174C>T	p.Pro392Ser	missense_variant	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 259 AN: 112577 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00463

GnomAD2 exomes AF: 0.00448 AC: 651 AN: 145314 AF XY: 0.00680

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00296

Gnomad EAS exome AF: 0.0000870

Gnomad FIN exome AF: 0.0000790

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00334 AC: 3618 AN: 1084502 Hom.: 15 Cov.: 55 AF XY: 0.00414 AC XY: 1463 AN XY: 353578

African (AFR) AF: 0.000230 AC: 6 AN: 26125

American (AMR) AF: 0.00163 AC: 55 AN: 33688

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 44 AN: 19116

East Asian (EAS) AF: 0.0000339 AC: 1 AN: 29520

South Asian (SAS) AF: 0.0248 AC: 1301 AN: 52481

European-Finnish (FIN) AF: 0.000342 AC: 13 AN: 38032

Middle Eastern (MID) AF: 0.00959 AC: 39 AN: 4065

European-Non Finnish (NFE) AF: 0.00240 AC: 2004 AN: 835952

Other (OTH) AF: 0.00340 AC: 155 AN: 45523

GnomAD4 genome AF: 0.00231 AC: 260 AN: 112625 Hom.: 1 Cov.: 24 AF XY: 0.00290 AC XY: 101 AN XY: 34781

African (AFR) AF: 0.000321 AC: 10 AN: 31156

American (AMR) AF: 0.00288 AC: 31 AN: 10775

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 7 AN: 2649

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3526

South Asian (SAS) AF: 0.0278 AC: 76 AN: 2738

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6206

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00235 AC: 125 AN: 53143

Other (OTH) AF: 0.00457 AC: 7 AN: 1532

Alfa AF: 0.00229 Hom.: 17

Bravo AF: 0.00176

ExAC AF: 0.00514 AC: 609

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:5

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AR p.Pro392Ser variant was identified in 4 of 584 proband chromosomes (frequency: 0.00685) from a Caucasian population presenting with isolated hypospadias without micropenis or cryptorchidism, and was not identified in 690 control chromosomes from healthy individuals (Kalfa_2013_23637914). The variant was also identified in dbSNP (ID: rs201934623) as "With Pathogenic allele" and ClinVar (3 submissions with conflicting interpretations of pathogenicity: Benign(1) by Genetic Services Laboratory, University of Chicago (2016); Pathogenic(1) by UCLA Clinical Genomics Center, UCLA - CES (2014); and Uncertain significance(1) by Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics (2018)). Submitters report the variant to be linked to Partial Androgen Insensitivity syndrome and Hypospadias 1, X-linked. The variant was also identified in Clinvitae, Cosmic, MutDB, and LOVD 3.0 (likely benign). The variant was identified in control databases in 684 of 166808 chromosomes (4 homozygous) at a frequency of 0.004101 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 404 of 16297 chromosomes (freq: 0.02479), Other in 16 of 4579 chromosomes (freq: 0.003494), Ashkenazi Jewish in 22 of 6922 chromosomes (freq: 0.003178), European (non-Finnish) in 189 of 71137 chromosomes (freq: 0.002657), Latino in 46 of 25450 chromosomes (freq: 0.001807), African in 5 of 14750 chromosomes (freq: 0.000339), East Asian in 1 of 12487 chromosomes (freq: 0.00008), and European (Finnish) in 1 of 15186 chromosomes (freq: 0.000066). Chakrabarty et al. identified the variant p.Pro392Ser as a somatic driver mutation in tissue samples of 18 long-standing ulcerative colitis (UC) subjects at high risk of colorectal carcinoma. (Chakrabarty_2017_28524162). The p.Pro392Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Chakrabarty, Sanjiban, et al. "Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia." British journal of cancer 117.1 (2017): 136. Kalfa, Nicolas, et al. "Minor hypospadias: the “tip of the iceberg” of the partial androgen insensitivity syndrome." PloS one 8.4 (2013): e61824. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AR: PM5, BS1 -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 20, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Androgen resistance syndrome Uncertain:1 Benign:2

Feb 28, 2024

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG:PM1 PP3 BS1 BP2 BP4 -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Partial androgen insensitivity syndrome Pathogenic:1

Jul 01, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypospadias 1, X-linked Uncertain:1

Jan 31, 2018

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant c.1174C>T (p.P392S) has the minor allele frequency of 0.74% in 1000 Genomes and 0.8% in ExAC databases. The in silico predictions of the variant is polymorphism by Mutation Taster, benign by PolyPhen and damaging by SIFT. -

not specified Benign:1

Sep 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AR-related disorder Benign:1

Jul 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome Benign:1

Feb 21, 2022

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.;.;.;T;.
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
MetaRNN	Benign	0.0063	T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
PhyloP100		1.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	.;N;D;D;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.023	.;D;T;D;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T
Vest4		0.071
MVP		0.98
MPC		0.49
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.091
gMVP		0.63
Mutation Taster		=75/25	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: rs201934623; hg19: chrX-66766162;