chrX-67546588-A-G

Position:

• chrX-67546588-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000374690.9(AR):​c.1442A>G​(p.Tyr481Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y481Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AR ENST00000374690.9 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.1442A>G	p.Tyr481Cys	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.1442A>G	p.Tyr481Cys	missense_variant	1/8	1	NM_000044.6	ENSP00000363822	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 21

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

May 30, 2016

This sequence change replaces tyrosine with cysteine at codon 481 of the AR protein (p.Tyr481Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a AR-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;.;T;.
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	.;D;D;D;.;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D;D;D;.;.
Sift4G	Uncertain	0.012	D;D;D;D;D;T
Vest4		0.44
MVP		0.98
MPC		1.2
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.83

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: rs1555970006; hg19: chrX-66766430;