chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T

Variant summary

Our verdict is Likely benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G462G) has been classified as Likely benign.

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

Publications

6 publications found
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 Gene-Disease associations (from GenCC):
  • androgen insensitivity syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • Kennedy disease
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • partial androgen insensitivity syndrome
    Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
  • complete androgen insensitivity syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1
Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 190 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. 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 rank MANE Protein UniProt
ARNM_000044.6 linkc.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG p.Gly462_Gly473del disruptive_inframe_deletion Exon 1 of 8 ENST00000374690.9 NP_000035.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkc.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG p.Gly462_Gly473del disruptive_inframe_deletion Exon 1 of 8 1 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.000265
AC:
22
AN:
83056
Hom.:
0
Cov.:
0
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
African (AFR)
AF:
0.000151
AC:
2
AN:
13218
American (AMR)
AF:
0.00303
AC:
26
AN:
8578
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
9545
East Asian (EAS)
AF:
0.00241
AC:
34
AN:
14084
South Asian (SAS)
AF:
0.00945
AC:
139
AN:
14707
European-Finnish (FIN)
AF:
0.000183
AC:
4
AN:
21856
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1303
European-Non Finnish (NFE)
AF:
0.000938
AC:
349
AN:
372150
Other (OTH)
AF:
0.000874
AC:
18
AN:
20591
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.688
Heterozygous variant carriers
0
10
19
29
38
48
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
African (AFR)
AF:
0.000185
AC:
4
AN:
21655
American (AMR)
AF:
0.000384
AC:
3
AN:
7817
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2222
East Asian (EAS)
AF:
0.00117
AC:
3
AN:
2564
South Asian (SAS)
AF:
0.00197
AC:
3
AN:
1520
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
2382
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
174
European-Non Finnish (NFE)
AF:
0.000209
AC:
9
AN:
43137
Other (OTH)
AF:
0.00
AC:
0
AN:
1076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
327

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
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

AR-related disorder Uncertain:1
Aug 23, 2022
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Androgen resistance syndrome Uncertain:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Androgen insensitivity, partial, with breast cancer Uncertain:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.3
Mutation Taster
=199/1
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356; API