chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-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.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG(p.Gly464_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 0.00151 in 559,079 control chromosomes in the GnomAD database, including 77 homozygotes. There are 244 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. G464G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., 21 hem., cov: 0)

Exomes 𝑓: 0.0016 ( 77 hom. 223 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

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 mid. GnomAdExome4 allele frequency = 0.0016 (764/476023) while in subpopulation MID AF = 0.0138 (18/1306). AF 95% confidence interval is 0.00891. There are 77 homozygotes in GnomAdExome4. There are 223 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 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_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.1391_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly464_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.000963

AC:

AN:

83052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00102

Gnomad ASJ

AF:

0.000450

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00513

Gnomad NFE

AF:

0.000811

Gnomad OTH

AF:

0.00283

GnomAD4 exome

AF:

0.00160

AC:

764

AN:

476023

Hom.:

AF XY:

0.00189

AC XY:

223

AN XY:

118101

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

13217

American (AMR)

AF:

0.00618

AC:

AN:

8578

Ashkenazi Jewish (ASJ)

AF:

0.000314

AC:

AN:

9541

East Asian (EAS)

AF:

0.00213

AC:

AN:

14079

South Asian (SAS)

AF:

0.00190

AC:

AN:

14705

European-Finnish (FIN)

AF:

0.0000915

AC:

AN:

21849

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

1306

European-Non Finnish (NFE)

AF:

0.00147

AC:

547

AN:

372162

Other (OTH)

AF:

0.00248

AC:

AN:

20586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.680

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:

0.000963

AC:

AN:

83056

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

16628

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

21655

American (AMR)

AF:

0.00102

AC:

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.000450

AC:

AN:

2222

East Asian (EAS)

AF:

0.00117

AC:

AN:

2563

South Asian (SAS)

AF:

0.00

AC:

AN:

1522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2382

Middle Eastern (MID)

AF:

0.00575

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000811

AC:

AN:

43132

Other (OTH)

AF:

0.00279

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

- -

AR-related disorder

Benign:1

Dec 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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