NM_000044.6:c.1139C>G

Variant names:

• chrX-67546285-C-G
• rs200510049
• NM_000044.6:c.1139C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000044.6(AR):​c.1139C>G​(p.Pro380Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,203,372 control chromosomes in the GnomAD database, including 2 homozygotes. There are 101 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 0.0018 (1 hom., 55 hem., cov: 24)
  • Exomes 𝑓: 0.00019 (1 hom. 46 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.06
• Publications: 3 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: Benign. The variant received -8 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=0.008013278).
• BP6: Variant X-67546285-C-G is Benign according to our data. Variant chrX-67546285-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434263.
• BS2: High Hemizygotes in GnomAd4 at 55 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.1139C>G	p.Pro380Arg	missense	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1139C>G	p.Pro380Arg	missense	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1139C>G	p.Pro380Arg	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.1139C>G	p.Pro380Arg	missense	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1139C>G	p.Pro380Arg	missense	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1139C>G	p.Pro380Arg	missense	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 205 AN: 112339 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000651

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: 0.0000188

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.000563 AC: 90 AN: 159885 AF XY: 0.000291

Gnomad AFR exome AF: 0.00772

Gnomad AMR exome AF: 0.000308

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: 0.000246

GnomAD4 exome AF: 0.000189 AC: 206 AN: 1090981 Hom.: 1 Cov.: 55 AF XY: 0.000129 AC XY: 46 AN XY: 357719

African (AFR) AF: 0.00609 AC: 160 AN: 26288

American (AMR) AF: 0.000347 AC: 12 AN: 34562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19243

East Asian (EAS) AF: 0.00 AC: 0 AN: 29904

South Asian (SAS) AF: 0.00 AC: 0 AN: 53095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 838977

Other (OTH) AF: 0.000546 AC: 25 AN: 45789

GnomAD4 genome AF: 0.00182 AC: 205 AN: 112391 Hom.: 1 Cov.: 24 AF XY: 0.00159 AC XY: 55 AN XY: 34575

African (AFR) AF: 0.00622 AC: 193 AN: 31041

American (AMR) AF: 0.000650 AC: 7 AN: 10764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53110

Other (OTH) AF: 0.00262 AC: 4 AN: 1525

Alfa AF: 0.000998 Hom.: 7

Bravo AF: 0.00199

ESP6500AA AF: 0.00632 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000531 AC: 64

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)
-	-	1	AR-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0080	T
MetaSVM	Pathogenic	0.90	D
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.32	T
Vest4		0.72
MVP		0.94
MPC		0.94
ClinPred		0.041	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.50
Mutation Taster		=91/9	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: rs200510049; hg19: chrX-66766127;