X-67694959-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000504326.5(AR):c.*237T>C variant causes a 3 prime UTR 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 ENST00000504326.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS2: High Homozygotes in GnomAd at 20321 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1885+8833T>C		intron_variant		ENST00000374690.9
AR	NM_001348061.1	c.*237T>C		3_prime_UTR_variant	4/4
AR	NM_001348064.1	c.*370T>C		3_prime_UTR_variant	3/3
AR	NM_001011645.3	c.289+8833T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1885+8833T>C		intron_variant		1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 72091 AN: 110400 Hom.: 20321 Cov.: 23 AF XY: 0.669 AC XY: 21829 AN XY: 32638

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

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.920

Gnomad4 FIN exome AF: 0.872

Gnomad4 NFE exome AF: 0.851

Gnomad4 OTH exome AF: 0.826

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

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.888

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.917

Gnomad4 FIN AF: 0.878

Gnomad4 NFE AF: 0.840

Gnomad4 OTH AF: 0.703

Alfa AF: 0.772 Hom.: 15737

Bravo AF: 0.635

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.5
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs5918762; hg19: chrX-66914801;