chrX-67698871-A-G

Variant names:

• chrX-67698871-A-G
• rs5919411
• NM_000044.6:c.1886-12531A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000044.6(AR):​c.1886-12531A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (27078 hom., 26780 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 5 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1886-12531A>G		intron_variant	Intron 3 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.290-12531A>G		intron_variant	Intron 4 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1886-12531A>G		intron_variant	Intron 3 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.1886-12531A>G		intron_variant	Intron 3 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*234-12531A>G		intron_variant	Intron 4 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.1886-12531A>G		intron_variant	Intron 3 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.819 AC: 90122 AN: 110086 Hom.: 27084 Cov.: 22

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.903

Gnomad AMR AF: 0.930

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.939

Gnomad FIN AF: 0.933

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.867

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.819 AC: 90159 AN: 110145 Hom.: 27078 Cov.: 22 AF XY: 0.826 AC XY: 26780 AN XY: 32409

African (AFR) AF: 0.529 AC: 15984 AN: 30209

American (AMR) AF: 0.930 AC: 9574 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 2497 AN: 2629

East Asian (EAS) AF: 0.999 AC: 3451 AN: 3454

South Asian (SAS) AF: 0.938 AC: 2378 AN: 2534

European-Finnish (FIN) AF: 0.933 AC: 5420 AN: 5809

Middle Eastern (MID) AF: 0.907 AC: 195 AN: 215

European-Non Finnish (NFE) AF: 0.923 AC: 48748 AN: 52827

Other (OTH) AF: 0.870 AC: 1301 AN: 1496

Alfa AF: 0.880 Hom.: 124523

Bravo AF: 0.810

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.82
PhyloP100		-0.22
Mutation Taster		=100/0	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: rs5919411; hg19: chrX-66918713;