X-67694959-T-C

Variant names:

• chrX-67694959-T-C
• rs5918762
• ENST00000514029.5:n.*653T>C

Variant summary

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

The ENST00000374690.9(AR):​c.1885+8833T>C 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 0.65 (20313 hom., 21842 hem., cov: 23)
  • Exomes 𝑓: 0.84 (227239 hom. 222499 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR ENST00000374690.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• Publications: 12 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=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374690.9. 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.1885+8833T>C		intron	N/A	NP_000035.2
	AR	NM_001348061.1		c.*237T>C		3_prime_UTR	Exon 4 of 4	NP_001334990.1
	AR	NM_001348064.1		c.*370T>C		3_prime_UTR	Exon 3 of 3	NP_001334993.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000514029.5	TSL:1	n.*653T>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000425199.1
	AR	ENST00000613054.2	TSL:1	n.*370T>C		non_coding_transcript_exon	Exon 3 of 3	ENSP00000479013.1
	AR	ENST00000504326.5	TSL:1	c.*237T>C		3_prime_UTR	Exon 4 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 72091 AN: 110400 Hom.: 20321 Cov.: 23

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.699

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.841 AC: 753785 AN: 896785 Hom.: 227239 Cov.: 31 AF XY: 0.848 AC XY: 222499 AN XY: 262269

African (AFR) AF: 0.115 AC: 2331 AN: 20214

American (AMR) AF: 0.878 AC: 10449 AN: 11900

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 10735 AN: 12118

East Asian (EAS) AF: 0.999 AC: 22994 AN: 23007

South Asian (SAS) AF: 0.920 AC: 25847 AN: 28101

European-Finnish (FIN) AF: 0.872 AC: 15743 AN: 18061

Middle Eastern (MID) AF: 0.805 AC: 1778 AN: 2208

European-Non Finnish (NFE) AF: 0.851 AC: 633166 AN: 743958

Other (OTH) AF: 0.826 AC: 30742 AN: 37218

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.653 AC: 72082 AN: 110455 Hom.: 20313 Cov.: 23 AF XY: 0.668 AC XY: 21842 AN XY: 32703

African (AFR) AF: 0.136 AC: 4147 AN: 30576

American (AMR) AF: 0.833 AC: 8604 AN: 10329

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 2317 AN: 2609

East Asian (EAS) AF: 0.998 AC: 3451 AN: 3457

South Asian (SAS) AF: 0.917 AC: 2320 AN: 2530

European-Finnish (FIN) AF: 0.878 AC: 5095 AN: 5804

Middle Eastern (MID) AF: 0.775 AC: 165 AN: 213

European-Non Finnish (NFE) AF: 0.840 AC: 44334 AN: 52767

Other (OTH) AF: 0.703 AC: 1050 AN: 1494

Alfa AF: 0.798 Hom.: 27051

Bravo AF: 0.635

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.56
PhyloP100		0.35
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: rs5918762; hg19: chrX-66914801;