Variant chrX-67546514-T-TGGCGGCGGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000044.6(AR):c.1412_1420dup(p.Gly471_Gly473dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G456G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 12 hom., 94 hem., cov: 0)

Exomes 𝑓: 0.0055 ( 22 hom. 583 hem. )

Failed GnomAD Quality Control

Consequence

AR
NM_000044.6 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.29

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant X-67546514-T-TGGCGGCGGC is Benign according to our data. Variant chrX-67546514-T-TGGCGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 638387.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00937 (778/83055) while in subpopulation AFR AF= 0.0171 (370/21649). AF 95% confidence interval is 0.0157. There are 12 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6 linkuse as main transcript	c.1412_1420dup	p.Gly471_Gly473dup	inframe_insertion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9 linkuse as main transcript	c.1412_1420dup	p.Gly471_Gly473dup	inframe_insertion	1/8	1	NM_000044.6	P1	P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00937

AC:

778

AN:

83051

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

AN XY:

16619

show subpopulations

Gnomad AFR

AF:

0.0171

Gnomad AMI

AF:

0.0409

Gnomad AMR

AF:

0.00922

Gnomad ASJ

AF:

0.00225

Gnomad EAS

AF:

0.00505

Gnomad SAS

AF:

0.0144

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.00542

Gnomad OTH

AF:

0.0104

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00550

AC:

2614

AN:

475547

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

583

AN XY:

117847

show subpopulations

Gnomad4 AFR exome

AF:

0.00999

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.000838

Gnomad4 EAS exome

AF:

0.000709

Gnomad4 SAS exome

AF:

0.00544

Gnomad4 FIN exome

AF:

0.000457

Gnomad4 NFE exome

AF:

0.00605

Gnomad4 OTH exome

AF:

0.00563

GnomAD4 genome

AF:

0.00937

AC:

778

AN:

83055

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

AN XY:

16629

show subpopulations

Gnomad4 AFR

AF:

0.0171

Gnomad4 AMR

AF:

0.00921

Gnomad4 ASJ

AF:

0.00225

Gnomad4 EAS

AF:

0.00507

Gnomad4 SAS

AF:

0.0145

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.00542

Gnomad4 OTH

AF:

0.0102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Androgen resistance syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2016

- -

AR-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over