X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000044.6(AR):​c.1415_1420delGCGGCG​(p.Gly472_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 0.0114 in 557,735 control chromosomes in the GnomAD database, including 418 homozygotes. There are 1,145 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 169 hom., 408 hem., cov: 0)
Exomes 𝑓: 0.0070 ( 249 hom. 737 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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 -16 ACMG points.

BP6
Variant X-67546514-TGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 434260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGCGGC-T is described in Lovd as [Likely_benign]. Variant chrX-67546514-TGGCGGC-T is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARNM_000044.6 linkc.1415_1420delGCGGCG p.Gly472_Gly473del disruptive_inframe_deletion 1/8 ENST00000374690.9 NP_000035.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARENST00000374690.9 linkc.1415_1420delGCGGCG p.Gly472_Gly473del disruptive_inframe_deletion 1/81 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.0363
AC:
3014
AN:
83027
Hom.:
169
Cov.:
0
AF XY:
0.0245
AC XY:
407
AN XY:
16611
show subpopulations
Gnomad AFR
AF:
0.127
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0138
Gnomad ASJ
AF:
0.000450
Gnomad EAS
AF:
0.00505
Gnomad SAS
AF:
0.00720
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00513
Gnomad NFE
AF:
0.00253
Gnomad OTH
AF:
0.0255
GnomAD4 exome
AF:
0.00700
AC:
3325
AN:
474704
Hom.:
249
AF XY:
0.00628
AC XY:
737
AN XY:
117274
show subpopulations
Gnomad4 AFR exome
AF:
0.122
Gnomad4 AMR exome
AF:
0.00596
Gnomad4 ASJ exome
AF:
0.00115
Gnomad4 EAS exome
AF:
0.00695
Gnomad4 SAS exome
AF:
0.00743
Gnomad4 FIN exome
AF:
0.00212
Gnomad4 NFE exome
AF:
0.00298
Gnomad4 OTH exome
AF:
0.0151
GnomAD4 genome
AF:
0.0364
AC:
3019
AN:
83031
Hom.:
169
Cov.:
0
AF XY:
0.0245
AC XY:
408
AN XY:
16621
show subpopulations
Gnomad4 AFR
AF:
0.127
Gnomad4 AMR
AF:
0.0139
Gnomad4 ASJ
AF:
0.000450
Gnomad4 EAS
AF:
0.00507
Gnomad4 SAS
AF:
0.00723
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00253
Gnomad4 OTH
AF:
0.0251

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 26, 2017- -
Androgen resistance syndrome;C1839259:Kennedy disease Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 13, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2019- -
AR-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 09, 2019This 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