rs137852584

chrX-67711459-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000044.6(AR):c.1943G>A(p.Ser648Asn) variant causes a missense 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S648S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0970

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-67711459-G-A is Pathogenic according to our data. Variant chrX-67711459-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9809.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-67711459-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.24616322).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1943G>A	p.Ser648Asn	missense_variant	4/8	ENST00000374690.9
AR	NM_001011645.3	c.347G>A	p.Ser116Asn	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1943G>A	p.Ser648Asn	missense_variant	4/8	1	NM_000044.6	P1
AR	ENST00000396044.8	c.1943G>A	p.Ser648Asn	missense_variant	4/5	1
AR	ENST00000396043.4	c.*291G>A		3_prime_UTR_variant, NMD_transcript_variant	5/9	1
AR	ENST00000612452.5	c.1943G>A	p.Ser648Asn	missense_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 25, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.3
Dann	Benign	0.94
DEOGEN2	Benign	0.020	T;.;.;.
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	0.00013	A;A;A
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.35	T;T;T;T
Vest4		0.096
MVP		0.80
MPC		0.37
ClinPred		0.054	T
GERP RS		2.5
Varity_R		0.093
gMVP		0.49

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: rs137852584; hg19: chrX-66931301; COSMIC: COSV65964464;