chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T

Variant names:

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

AR links:

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
AR	NM_000044.6 link	c.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
AR	ENST00000374690.9 link	c.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:

AN:

83056

Hom.:

Cov.:

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.:

AF XY:

0.00161

AC XY:

190

AN XY:

118084

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

13218

American (AMR)

AF:

0.00303

AC:

AN:

8578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9545

East Asian (EAS)

AF:

0.00241

AC:

AN:

14084

South Asian (SAS)

AF:

0.00945

AC:

139

AN:

14707

European-Finnish (FIN)

AF:

0.000183

AC:

AN:

21856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1303

European-Non Finnish (NFE)

AF:

0.000938

AC:

349

AN:

372150

Other (OTH)

AF:

0.000874

AC:

AN:

20591

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.688

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

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:

AN:

83060

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

AN XY:

16632

show subpopulations

African (AFR)

AF:

0.000185

AC:

AN:

21655

American (AMR)

AF:

0.000384

AC:

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2222

East Asian (EAS)

AF:

0.00117

AC:

AN:

2564

South Asian (SAS)

AF:

0.00197

AC:

AN:

1520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000209

AC:

AN:

43137

Other (OTH)

AF:

0.00

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over