rs137852595

Positions:

• chrX-67711653-C-A
• chrX-67711653-C-G
• chrX-67711653-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000044.6(AR):​c.2137C>A​(p.Leu713Ile) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L713F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11

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 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chrX-67711653-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9852.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant X-67711653-C-A is Pathogenic according to our data. Variant chrX-67711653-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 391803.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2137C>A	p.Leu713Ile	missense_variant	4/8	ENST00000374690.9
AR	NM_001011645.3	c.541C>A	p.Leu181Ile	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2137C>A	p.Leu713Ile	missense_variant	4/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2137C>A	p.Leu713Ile	missense_variant	4/5	1
AR	ENST00000396043.4	c.*485C>A		3_prime_UTR_variant, NMD_transcript_variant	5/9	1
AR	ENST00000612452.5	c.2137C>A	p.Leu713Ile	missense_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2016

The L713I variant in the AR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L713I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L713I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position within the ligand-binding region that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants at this residue (L713V, L713F) and in nearby residues (L708R, G709E, G709A, G709V, E710K, R711T, Q712E) have been reported in the Human Gene Mutation Database in association with androgen insensitivity syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the available evidence, we interpret L713I as a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	.;N;N;N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	.;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Vest4		0.70
MVP		0.98
MPC		1.3
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.91

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: rs137852595; hg19: chrX-66931495;