X-67717561-C-T

Position:

• chrX-67717561-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000044.6(AR):​c.2257C>T​(p.Arg753*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,999 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: AR NM_000044.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.15

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-67717561-C-T is Pathogenic according to our data. Variant chrX-67717561-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67717561-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2257C>T	p.Arg753*	stop_gained	5/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.661C>T	p.Arg221*	stop_gained	6/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2257C>T	p.Arg753*	stop_gained	5/8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097999 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363383

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Genetics Department, Polish Mother's Memorial Hospital Research Institute	Jul 04, 2024	The patient is a 35-year-old phenotypically female with 46,XY karyotype, and typical symptoms of complete androgen insensitivity syndrome. The detected NM_000044.6:c.2257C>T p.(Arg753*) variant causes a stop-gained change involving the alteration of a non-conserved nucleotide. The variant results in nonsense-mediated mRNA decay. The variant allele was found at a frequency of 0.000001650 in the GnomAD v4.1.0 database, with no homozygous or hemizygous occurrences. The in-silico tools predicted a pathogenic outcome for this variant. The variant has been reported three times in ClinVar as pathogenic. The variant was classified as pathogenic with 14 ACMG points (criteria: PVS1, PS4_moderate, PM2, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Mar 25, 2020	The AR p.Gly709Glu variant replaces the glycine at position 709 with glutamic acid. This variant has been reported in the literature as a pathogenic change in an individual with complete androgen insensitivity (PMID: 20671138). This variant has not been observed in the Genome Aggregation Database (0 of approx. 178,000 alleles; v2.1). Further supporting pathogenicity, different missense changes at the same residue (p.Gly709Ala, p.Gly709Val, p.Gly709Arg) have also been reported as pathogenic in individuals with androgen insensitivity syndrome (complete, partial, and mild AIS) (PMID: 10840043, PMID: 22334387, PMID: 7981687). -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 265460). This premature translational stop signal has been observed in individual(s) with complete androgen insensitivity syndrome (CAIS) (PMID: 10458483, 12843171, 15925895). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg753*) in the AR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AR are known to be pathogenic (PMID: 19463997). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2018

The R753X nonsense variant in the AR gene has been reported previously as R752X using alternate nomenclature in association with androgen insensitivity syndrome (Yaegashi et al., 1999; Ledig et al., 2005). The 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. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.98
GERP RS		1.9

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: rs886039558; hg19: chrX-66937403; COSMIC: COSV65953893;