rs9332971

Positions:

• chrX-67722944-G-A
• chrX-67722944-G-C
• chrX-67722944-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000044.6(AR):​c.2567G>A​(p.Arg856His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R856C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 16 ACMG points.

• PM1: In a helix (size 30) in uniprot entity ANDR_HUMAN there are 26 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 chrX-67722943-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant X-67722944-G-A is Pathogenic according to our data. Variant chrX-67722944-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67722944-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.2567G>A	p.Arg856His	missense_variant	7/8	ENST00000374690.9
AR	NM_001011645.3	c.971G>A	p.Arg324His	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.2567G>A	p.Arg856His	missense_variant	7/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.2174-742G>A		intron_variant		1
AR	ENST00000396043.4	c.*915G>A		3_prime_UTR_variant, NMD_transcript_variant	8/9	1
AR	ENST00000612452.5	c.2567G>A	p.Arg856His	missense_variant, NMD_transcript_variant	7/9	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 20, 2023	ACMG:PM1 PM2 PP3 PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jul 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

Partial androgen insensitivity syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1993

- -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg856 amino acid residue in AR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581399, 24321103). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9823). This variant is also known as R853H and 2926G>A (R855H). This missense change has been observed in individuals with partial androgen insensitivity syndrome (PMID: 1430233, 8097257, 24737579). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 856 of the AR protein (p.Arg856His). -

Male infertility Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;research

Institute of Reproductive Genetics, University of Münster

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.86	D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.90
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.98

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; COSMIC: COSV101018027;