rs1555969722

Positions:

• chrX-67546095-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000044.6(AR):​c.949A>G​(p.Thr317Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05650118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.949A>G	p.Thr317Ala	missense_variant	1/8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.949A>G	p.Thr317Ala	missense_variant	1/8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with AR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 317 of the AR protein (p.Thr317Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.025
DANN	Benign	0.58
DEOGEN2	Benign	0.0068	T;.;.;.;T;.
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.057	T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.080	.;N;N;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.87	.;T;T;T;.;.
Sift4G	Benign	0.96	T;T;T;T;T;T
Vest4		0.066
MVP		0.65
MPC		0.39
ClinPred		0.040	T
GERP RS		-5.0
Varity_R		0.042
gMVP		0.14

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: rs1555969722; hg19: chrX-66765937; COSMIC: COSV101019541;