NM_000044.6:c.1937C>A

Variant names:

• chrX-67711453-C-A
• rs1800053
• NM_000044.6:c.1937C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000044.6(AR):​c.1937C>A​(p.Ala646Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,202,319 control chromosomes in the GnomAD database, including 2 homozygotes. There are 764 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 37 hem., cov: 23)
  • Exomes 𝑓: 0.0021 (2 hom. 727 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 0.405
• Publications: 14 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, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

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

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• 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=0.17819354).
• BP6: Variant X-67711453-C-A is Benign according to our data. Variant chrX-67711453-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9861.
• BS2: High Hemizygotes in GnomAd4 at 37 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1937C>A	p.Ala646Asp	missense	Exon 4 of 8	NP_000035.2
	AR	NM_001011645.3		c.341C>A	p.Ala114Asp	missense	Exon 5 of 9	NP_001011645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1937C>A	p.Ala646Asp	missense	Exon 4 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.1937C>A	p.Ala646Asp	missense	Exon 4 of 5	ENSP00000379359.3
	AR	ENST00000396043.4	TSL:1	n.*285C>A		non_coding_transcript_exon	Exon 5 of 9	ENSP00000379358.4

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 135 AN: 112131 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000945

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00113 AC: 185 AN: 163917 AF XY: 0.00112

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.000155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000408

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.00214 AC: 2333 AN: 1090188 Hom.: 2 Cov.: 31 AF XY: 0.00204 AC XY: 727 AN XY: 357196

African (AFR) AF: 0.0000761 AC: 2 AN: 26298

American (AMR) AF: 0.000146 AC: 5 AN: 34313

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19240

East Asian (EAS) AF: 0.00 AC: 0 AN: 29936

South Asian (SAS) AF: 0.00 AC: 0 AN: 52670

European-Finnish (FIN) AF: 0.000450 AC: 18 AN: 40036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.00269 AC: 2255 AN: 837755

Other (OTH) AF: 0.00116 AC: 53 AN: 45815

GnomAD4 genome AF: 0.00120 AC: 135 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00108 AC XY: 37 AN XY: 34299

African (AFR) AF: 0.000162 AC: 5 AN: 30803

American (AMR) AF: 0.0000945 AC: 1 AN: 10579

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00240 AC: 128 AN: 53287

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00130 Hom.: 12

Bravo AF: 0.00112

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00121 AC: 146

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)
-	-	1	AR-related disorder (1)
-	1	-	Castleman-Kojima disease (1)
-	1	-	Male infertility (1)
-	-	1	not specified (1)
1	-	-	Partial androgen insensitivity syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0068	T
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.57	T
PhyloP100		0.41
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.58
Sift	Benign	0.035	D
Sift4G	Benign	0.56	T
Vest4		0.70
MVP		0.96
MPC		0.68
ClinPred		0.0084	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.61
Mutation Taster		=86/14	polymorphism (auto)

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: rs1800053; hg19: chrX-66931295; COSMIC: COSV65953758;