X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000044.6(AR):​c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly466_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 0.00268 in 559,009 control chromosomes in the GnomAD database, including 125 homozygotes. There are 397 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., 44 hem., cov: 0)
Exomes 𝑓: 0.0026 ( 123 hom. 353 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

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 Benign. Variant got -10 ACMG points.

BP6
Variant X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1167648.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign]. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00293 (243/83056) while in subpopulation AFR AF= 0.00697 (151/21650). AF 95% confidence interval is 0.00607. There are 2 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARNM_000044.6 linkc.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG p.Gly466_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.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG p.Gly466_Gly473del disruptive_inframe_deletion Exon 1 of 8 1 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.00293
AC:
243
AN:
83052
Hom.:
2
Cov.:
0
AF XY:
0.00259
AC XY:
43
AN XY:
16616
show subpopulations
Gnomad AFR
AF:
0.00693
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00243
Gnomad ASJ
AF:
0.00495
Gnomad EAS
AF:
0.000777
Gnomad SAS
AF:
0.00131
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00513
Gnomad NFE
AF:
0.00125
Gnomad OTH
AF:
0.00377
GnomAD3 exomes
AF:
0.00532
AC:
200
AN:
37570
Hom.:
64
AF XY:
0.00339
AC XY:
44
AN XY:
12980
show subpopulations
Gnomad AFR exome
AF:
0.0871
Gnomad AMR exome
AF:
0.00935
Gnomad ASJ exome
AF:
0.00606
Gnomad EAS exome
AF:
0.0341
Gnomad SAS exome
AF:
0.00181
Gnomad FIN exome
AF:
0.000132
Gnomad NFE exome
AF:
0.00386
Gnomad OTH exome
AF:
0.00304
GnomAD4 exome
AF:
0.00263
AC:
1253
AN:
475953
Hom.:
123
AF XY:
0.00299
AC XY:
353
AN XY:
118113
show subpopulations
Gnomad4 AFR exome
AF:
0.0111
Gnomad4 AMR exome
AF:
0.00502
Gnomad4 ASJ exome
AF:
0.00649
Gnomad4 EAS exome
AF:
0.00298
Gnomad4 SAS exome
AF:
0.00320
Gnomad4 FIN exome
AF:
0.000137
Gnomad4 NFE exome
AF:
0.00227
Gnomad4 OTH exome
AF:
0.00287
GnomAD4 genome
AF:
0.00293
AC:
243
AN:
83056
Hom.:
2
Cov.:
0
AF XY:
0.00265
AC XY:
44
AN XY:
16626
show subpopulations
Gnomad4 AFR
AF:
0.00697
Gnomad4 AMR
AF:
0.00243
Gnomad4 ASJ
AF:
0.00495
Gnomad4 EAS
AF:
0.000780
Gnomad4 SAS
AF:
0.00131
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00125
Gnomad4 OTH
AF:
0.00372

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1
Nov 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

AR-related disorder Benign:1
Sep 26, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as 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

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