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
NM_000044.6 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.29
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 |
---|---|---|---|---|---|---|---|---|
AR | NM_000044.6 | c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG | p.Gly462_Gly473del | disruptive_inframe_deletion | 1/8 | ENST00000374690.9 | NP_000035.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000265 AC: 22AN: 83056Hom.: 0 Cov.: 0 AF XY: 0.000301 AC XY: 5AN XY: 16622
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GnomAD4 exome AF: 0.00120 AC: 572AN: 476032Hom.: 55 AF XY: 0.00161 AC XY: 190AN XY: 118084
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GnomAD4 genome AF: 0.000265 AC: 22AN: 83060Hom.: 0 Cov.: 0 AF XY: 0.000301 AC XY: 5AN XY: 16632
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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 submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Androgen resistance syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Androgen insensitivity, partial, with breast cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
AR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 23, 2022 | The 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at