NM_000044.6:c.2612C>G

Variant names:

• chrX-67723690-C-G
• rs143040492
• NM_000044.6:c.2612C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_000044.6(AR):​c.2612C>G​(p.Ala871Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A871V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.66
• Publications: 0 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-67723690-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 492801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant X-67723690-C-G is Pathogenic according to our data. Variant chrX-67723690-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3362262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2612C>G	p.Ala871Gly	missense_variant	Exon 8 of 8	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.1016C>G	p.Ala339Gly	missense_variant	Exon 9 of 9		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2612C>G	p.Ala871Gly	missense_variant	Exon 8 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Partial androgen insensitivity syndrome Pathogenic:1

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.2612C>G(p.Ala871Gly) variant position in AR gene has been reported previously in X-linked state in individual(s) affected with androgen insensitivity syndrome (AIS) or sexual development disorder (Su et al., 2017; Chen et al., 2021). This variant is absent in gnomAD Exomes. This c.2612C>G(p.Ala871Gly) variant has not been reported to the ClinVar database, but this variant position c.2612C>T (p.Ala871Val) has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Ala at position 871 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala871Gly in AR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (SIFT Prediction - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. This variant disrupts the p.Ala871 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (Knoke et al., 1997). For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	0.052	D
PhyloP100		4.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	.;N;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.43
MVP		1.0
MPC		1.2
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.87
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143040492; hg19: chrX-66943532;