X-67723745-C-T

Variant names:

• chrX-67723745-C-T
• rs137852594
• NM_000044.6:c.2667C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000044.6(AR):​c.2667C>T​(p.Ser889Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: AR NM_000044.6 synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.58

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-67723745-C-T is Pathogenic according to our data. Variant chrX-67723745-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67723745-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2667C>T	p.Ser889Ser	synonymous_variant	Exon 8 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.1071C>T	p.Ser357Ser	synonymous_variant	Exon 9 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2667C>T	p.Ser889Ser	synonymous_variant	Exon 8 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate activation of a cryptic splice donor site and subsequent alternative splicing (Hellwinkel et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Also known as S888S; This variant is associated with the following publications: (PMID: 11587068, 11397856, 33505695, 20150575) -

Nov 22, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AR c.2667C>T (p.Ser889=) synonymous variant results in the substitution of cytosine at nucleotide position 2667 with thymine. Across a selection of the available literature, the c.2667C>T variant has been identified in a hemizygous state in at least four individuals with androgen insensitivity syndrome, characterized by atypical genitalia, hypospadias, low levels of luteinizing and follicle stimulating hormone, and cryptorchidism (PMID: 11397856, 28743543, 33505695, 35561789). The variant segregated in three affected males and unaffected carrier mothers in a multi-generational family (PMID: 35561789). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrated that the c.2667C>T variant produces an aberrant splicing variant that leads to partial skipping of exon 8 and a shortened 3'-untranslated region and the androgen-induced transcriptional activity is inhibited (PMID: 11397856). Based on the available evidence, the c.2667C>T (p.Ser889=) variant is classified as pathogenic for androgen insensitivity syndrome. -

Androgen resistance syndrome Pathogenic:2

Nov 27, 2001

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 889 of the AR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the AR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with partial androgen insensitivity syndrome (PMID: 1158706, 11397856, 20150575). ClinVar contains an entry for this variant (Variation ID: 9850). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11397856). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852594; hg19: chrX-66943587; COSMIC: COSV65957365;