rs137852571

chrX-67717495-G-AchrX-67717495-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000044.6(AR):c.2191G>A(p.Val731Met) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,210,381 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 11 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1
• Conservation: PhyloP100: 4.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000044.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.21336913).
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2191G>A	p.Val731Met	missense_variant	5/8	ENST00000374690.9
AR	NM_001011645.3	c.595G>A	p.Val199Met	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2191G>A	p.Val731Met	missense_variant	5/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2173+5806G>A		intron_variant		1
AR	ENST00000396043.4	c.*539G>A		3_prime_UTR_variant, NMD_transcript_variant	6/9	1
AR	ENST00000612452.5	c.2191G>A	p.Val731Met	missense_variant, NMD_transcript_variant	5/9	5

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112311 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34481

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000842

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000766 AC: 14 AN: 182820 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000725

Gnomad SAS exome AF: 0.0000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1098018 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 11 AN XY: 363412

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112363 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34543

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000845

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Prostate cancer, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1995

- -

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.0052	T
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.077	T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.78	T
Sift4G	Uncertain	0.042	D;D;D
Vest4		0.71
MVP		0.98
MPC		0.46
ClinPred		0.083	T
GERP RS		5.0
Varity_R		0.78
gMVP		0.87

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

Other links and lift over

dbSNP: rs137852571; hg19: chrX-66937337; COSMIC: COSV65955393;