X-67721755-T-G

Position:

• chrX-67721755-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000044.6(AR):​c.2319-78T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (32800 hom., 29722 hem., cov: 22)
  • Exomes 𝑓: 0.99 (355706 hom. 339294 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.963

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-67721755-T-G is Benign according to our data. Variant chrX-67721755-T-G is described in ClinVar as [Benign]. Clinvar id is 1239857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AR	NM_000044.6	c.2319-78T>G		intron_variant		ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.723-78T>G		intron_variant			NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2319-78T>G		intron_variant		1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2174-1931T>G		intron_variant		1		ENSP00000379359.3
AR	ENST00000396043.4	n.*667-78T>G		intron_variant		1		ENSP00000379358.4
AR	ENST00000612452.5	n.2319-78T>G		intron_variant		5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.909 AC: 100296 AN: 110307 Hom.: 32807 Cov.: 22 AF XY: 0.913 AC XY: 29675 AN XY: 32511

Gnomad AFR AF: 0.685

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.966

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.937

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.990 AC: 1056153 AN: 1066293 Hom.: 355706 AF XY: 0.992 AC XY: 339294 AN XY: 341887

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.984

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.998

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.977

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.909 AC: 100332 AN: 110358 Hom.: 32800 Cov.: 22 AF XY: 0.913 AC XY: 29722 AN XY: 32572

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.967

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.938

Alfa AF: 0.938 Hom.: 9775

Bravo AF: 0.897

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.61
DANN	Benign	0.36

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: rs1337076; hg19: chrX-66941597;