X-67722944-G-T

Position:

• chrX-67722944-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000044.6(AR):​c.2567G>T​(p.Arg856Leu) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-67722944-G-T is Pathogenic according to our data. Variant chrX-67722944-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 279688.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2567G>T	p.Arg856Leu	missense_variant	7/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.971G>T	p.Arg324Leu	missense_variant	8/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2567G>T	p.Arg856Leu	missense_variant	7/8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2015

R856L has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge.R856L represents a nonconservative amino acid substitution in the highly conservedligand binding domain of the protein. Other variants at the same codon (R856C, R856H, R856G) have been reported in association with androgen insensitivity syndrome. Functional studies of the R856C and R856H variants indicate impairment of androgen binding capacity (de Bellis et al., 1992; Batch et al., 1992; Ahmed et al., 2000; Bouvattier et al., 2002; Melo et al., 2003). The NHLBI ESP Exome Variant Server reports R856L was not observed in approximately 6,500 samples from individuals of European and African Americanbackgrounds, indicating it is not a common benign variant in these populations. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.3	.;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.97
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

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: rs9332971; hg19: chrX-66942786;