rs137852593

Variant names:

• chrX-67717484-G-A
• rs137852593
• NM_000044.6:c.2180G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-67717484-G-A
• chrX-67717484-G-T
• chrX-67717484-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_000044.6(AR):​c.2180G>A​(p.Arg727His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,097,894 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R727L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000033 (0 hom. 12 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 12 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000044.6
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

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.2180G>A	p.Arg727His	missense	Exon 5 of 8	NP_000035.2
	AR	NM_001011645.3		c.584G>A	p.Arg195His	missense	Exon 6 of 9	NP_001011645.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.2180G>A	p.Arg727His	missense	Exon 5 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.2173+5795G>A		intron	N/A	ENSP00000379359.3	F5GZG9
	AR	ENST00000396043.4	TSL:1	n.*528G>A		non_coding_transcript_exon	Exon 6 of 9	ENSP00000379358.4	A0A7I2PS51

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 112216 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000219 AC: 4 AN: 182614 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 36 AN: 1097894 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 12 AN XY: 363316

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30177

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54102

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.0000392 AC: 33 AN: 842013

Other (OTH) AF: 0.0000217 AC: 1 AN: 46074

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 112216 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34374

African (AFR) AF: 0.00 AC: 0 AN: 30845

American (AMR) AF: 0.00 AC: 0 AN: 10651

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6149

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53216

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.00 Hom.: 8

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.55
MVP		1.0
MPC		1.4
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.92
Mutation Taster		=71/29	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: rs137852593; hg19: chrX-66937326;