NM_000044.6:c.173A>T

Variant names:

• chrX-67545319-A-T
• rs200185441
• NM_000044.6:c.173A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS2_Supporting

The NM_000044.6(AR):​c.173A>T​(p.Gln58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 400,868 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q58R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.000072 (0 hom. 2 hem.)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 O:1
• Conservation: PhyloP100: 1.40
• Publications: 21 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 -2 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, complete androgen insensitivity syndrome, Kennedy disease, partial androgen insensitivity syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19961861).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.173A>T	p.Gln58Leu	missense	Exon 1 of 8	NP_000035.2
	AR	NM_001011645.3		c.-1611A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001011645.1	Q9NUA2
	AR	NM_001348063.1		c.173A>T	p.Gln58Leu	missense	Exon 1 of 4	NP_001334992.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.173A>T	p.Gln58Leu	missense	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.173A>T	p.Gln58Leu	missense	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.173A>T	p.Gln58Leu	missense	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.000429 AC: 10 AN: 23306 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00154

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000736

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000239

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000126 AC: 7 AN: 55672 AF XY: 0.0000451

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000468

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 27 AN: 377568 Hom.: 0 Cov.: 39 AF XY: 0.0000198 AC XY: 2 AN XY: 101182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4141

American (AMR) AF: 0.000159 AC: 2 AN: 12581

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7743

East Asian (EAS) AF: 0.0000813 AC: 1 AN: 12302

South Asian (SAS) AF: 0.00 AC: 0 AN: 21713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12689

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1022

European-Non Finnish (NFE) AF: 0.0000759 AC: 22 AN: 289886

Other (OTH) AF: 0.000129 AC: 2 AN: 15491

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000429 AC: 10 AN: 23300 Hom.: 0 Cov.: 0 AF XY: 0.000149 AC XY: 1 AN XY: 6698

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000342 AC: 1 AN: 2922

American (AMR) AF: 0.00154 AC: 5 AN: 3242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 886

East Asian (EAS) AF: 0.000741 AC: 1 AN: 1350

South Asian (SAS) AF: 0.00 AC: 0 AN: 553

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.000239 AC: 3 AN: 12568

Other (OTH) AF: 0.00 AC: 0 AN: 355

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000226866), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000253 Hom.: 0

ExAC AF: 0.0000207 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome;C0376358:Prostate cancer;C1839259:Kennedy disease;C2678098:Hypospadias 1, X-linked (1)
-	1	-	Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome;C1839259:Kennedy disease;C2678098:Hypospadias 1, X-linked;C2931456:Familial prostate cancer (1)
1	-	-	Male infertility (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Partial androgen insensitivity syndrome;C5231010:Posterior hypospadias (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.18	T
Vest4		0.75
MVP		0.93
MPC		0.39
ClinPred		0.047	T
PromoterAI		-0.0011	Neutral
Varity_R		0.19
gMVP		0.71
Mutation Taster		=99/1	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: rs200185441; hg19: chrX-66765161; COSMIC: COSV65953279;