rs1555997580

Positions:

• chrX-67721873-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.2359C>T​(p.Arg787Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.255

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-67721873-C-T is Pathogenic according to our data. Variant chrX-67721873-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 458364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67721873-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.2359C>T	p.Arg787Ter	stop_gained	6/8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.763C>T	p.Arg255Ter	stop_gained	7/9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2359C>T	p.Arg787Ter	stop_gained	6/8	1	NM_000044.6	ENSP00000363822	P1
AR	ENST00000396044.8	c.2174-1813C>T		intron_variant		1		ENSP00000379359
AR	ENST00000396043.4	c.*707C>T		3_prime_UTR_variant, NMD_transcript_variant	7/9	1		ENSP00000379358
AR	ENST00000612452.5	c.2359C>T	p.Arg787Ter	stop_gained, NMD_transcript_variant	6/9	5		ENSP00000484033

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

ClinVar contains an entry for this variant (Variation ID: 458364). For these reasons, this variant has been classified as Pathogenic. This variant is also known as R785Ter. This premature translational stop signal has been observed in individual(s) with disorders of sex development (PMID: 1458719, 26980296). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg787*) 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

Genetic Services Laboratory, University of Chicago

Mar 17, 2020

DNA sequence analysis of the AR gene demonstrated a sequence change, c.2359C>T, which results in the creation of a premature stop codon at amino acid position 787, p.Arg787*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated AR protein with potentially abnormal function. This sequence change has previously been described in a patient with complete androgen insensitivity syndrome (CAIS) who presented with normal female genitalia, and absent müllerian derivatives (PMID: 31499074). Dong et al., 2016 also reported this sequence change in a patient with female external genitalia, no uterus, ovotestis with fallopian tube, primary amenorrhea and 46,XY karyotype (PMID: 26980296). This sequence change is absent from the large population databases (ExAC and gnomAD). These collective evidences indicate that this sequence change is pathogenic; however functional studies have not been performed to prove this conclusively. -

Androgen resistance syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

The p.Arg787* variant introduces a premature stop codon at amino acid position 787 within exon six (of eight total exons) and is predicted to result in loss-of-function of the androgen receptor. This variant has been observed in multiple unrelated individuals with differences in sex development (DSD), including androgen insensitivity syndrome (AIS, MIM #300068) (PMID: 26980296, PMID: 31499074). Loss-of-function is an established disease mechanism of AIS and other nonsense and frameshift variants in this region have been reported in affected individuals (PMID: 15724799, PMID: 30668521). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.65	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.99
GERP RS		1.7

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: rs1555997580; hg19: chrX-66941715; COSMIC: COSV101019190;