X-67722976-G-T

Position:

• chrX-67722976-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000044.6(AR):​c.2599G>T​(p.Val867Leu) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V867E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.18

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 30) in uniprot entity ANDR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant X-67722976-G-T is Pathogenic according to our data. Variant chrX-67722976-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9822.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-67722976-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28545392). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2599G>T	p.Val867Leu	missense_variant	7/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.1003G>T	p.Val335Leu	missense_variant	8/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2599G>T	p.Val867Leu	missense_variant	7/8	1	NM_000044.6	ENSP00000363822	P1
AR	ENST00000396044.8	c.2174-710G>T		intron_variant		1		ENSP00000379359
AR	ENST00000396043.4	c.*947G>T		3_prime_UTR_variant, NMD_transcript_variant	8/9	1		ENSP00000379358
AR	ENST00000612452.5	c.2599G>T	p.Val867Leu	missense_variant, NMD_transcript_variant	7/9	5		ENSP00000484033

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Partial androgen insensitivity syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.0028	T;.;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.46	.;N;N
REVEL	Uncertain	0.56
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.74
MVP		0.99
MPC		0.57
ClinPred		0.59	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.84

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: rs137852564; hg19: chrX-66942818;