rs865948546

Variant names:

• chrX-67545567-G-A
• rs865948546
• NM_000044.6:c.421G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-67545567-G-A
• chrX-67545567-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_000044.6(AR):​c.421G>A​(p.Ala141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,069,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.334
• Publications: 1 publications found

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]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.073743165).
• BP6: Variant X-67545567-G-A is Benign according to our data. Variant chrX-67545567-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 434258.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	NP_001334990.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.421G>A	p.Ala141Thr	missense	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.421G>A	p.Ala141Thr	missense	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.421G>A	p.Ala141Thr	missense	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000230 AC: 3 AN: 130472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 3 AN: 1069951 Hom.: 0 Cov.: 55 AF XY: 0.00 AC XY: 0 AN XY: 347505

African (AFR) AF: 0.00 AC: 0 AN: 25816

American (AMR) AF: 0.0000973 AC: 3 AN: 30827

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18812

East Asian (EAS) AF: 0.00 AC: 0 AN: 28677

South Asian (SAS) AF: 0.00 AC: 0 AN: 51072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37993

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827761

Other (OTH) AF: 0.00 AC: 0 AN: 45003

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.9
DANN	Benign	0.82
DEOGEN2	Benign	0.0099	T
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.44	T
PhyloP100		-0.33
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.14
Sift	Benign	0.58	T
Sift4G	Benign	0.57	T
Vest4		0.053
MVP		0.77
MPC		0.39
ClinPred		0.016	T
GERP RS		0.22
PromoterAI		-0.075	Neutral
Varity_R		0.042
gMVP		0.34
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs865948546; hg19: chrX-66765409; COSMIC: COSV101018702;