X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000044.6(AR):​c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly462_Gly473del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 559,092 control chromosomes in the GnomAD database, including 55 homozygotes. There are 195 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 5 hem., cov: 0)
Exomes 𝑓: 0.0012 ( 55 hom. 190 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0012 (572/476032) while in subpopulation SAS AF= 0.00945 (139/14707). AF 95% confidence interval is 0.00817. There are 55 homozygotes in gnomad4_exome. There are 190 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARNM_000044.6 linkc.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG p.Gly462_Gly473del disruptive_inframe_deletion 1/8 ENST00000374690.9 NP_000035.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkc.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG p.Gly462_Gly473del disruptive_inframe_deletion 1/81 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.000265
AC:
22
AN:
83056
Hom.:
0
Cov.:
0
AF XY:
0.000301
AC XY:
5
AN XY:
16622
show subpopulations
Gnomad AFR
AF:
0.000185
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000384
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00117
Gnomad SAS
AF:
0.00197
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000209
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00120
AC:
572
AN:
476032
Hom.:
55
AF XY:
0.00161
AC XY:
190
AN XY:
118084
show subpopulations
Gnomad4 AFR exome
AF:
0.000151
Gnomad4 AMR exome
AF:
0.00303
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00241
Gnomad4 SAS exome
AF:
0.00945
Gnomad4 FIN exome
AF:
0.000183
Gnomad4 NFE exome
AF:
0.000938
Gnomad4 OTH exome
AF:
0.000874
GnomAD4 genome
AF:
0.000265
AC:
22
AN:
83060
Hom.:
0
Cov.:
0
AF XY:
0.000301
AC XY:
5
AN XY:
16632
show subpopulations
Gnomad4 AFR
AF:
0.000185
Gnomad4 AMR
AF:
0.000384
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00117
Gnomad4 SAS
AF:
0.00197
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000209
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypospadias 1, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
Androgen resistance syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
Androgen insensitivity, partial, with breast cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
AR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 23, 2022The AR c.1385_1420del36 variant is predicted to result in an in-frame deletion (p.Gly462_Gly473del). This variant occurs within an exon 1 polyglycine track and leads to deletion of 12 glycine residues. This polyglycine track occurs downstream of the polyglutamine track where expansions are causative for spinal and bulbar muscular atrophy. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. However, there is some evidence in the literature suggesting that shorter polyglycine tracks may also be associated with AR-related disease (Werner et al. 2006. PubMed ID: 16804045; Hakimi et al. 1997. PubMed ID: 9815849). This variant has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/587547/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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.

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356; API