X-67545316-T-TGCTGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_000044.6(AR):​c.172_173insTGCAGCAGC​(p.Leu57_Gln58insLeuGlnGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,003,921 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 0 hem., cov: 0)
Exomes 𝑓: 0.000041 ( 0 hom. 3 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.337
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 Likely_benign. Variant got -2 ACMG points.

BP6
Variant X-67545316-T-TGCTGCAGCA is Benign according to our data. Variant chrX-67545316-T-TGCTGCAGCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464788.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Hemizygotes in GnomAdExome4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARNM_000044.6 linkc.172_173insTGCAGCAGC p.Leu57_Gln58insLeuGlnGln disruptive_inframe_insertion 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.172_173insTGCAGCAGC p.Leu57_Gln58insLeuGlnGln disruptive_inframe_insertion Exon 1 of 8 1 NM_000044.6 ENSP00000363822.3 P10275-1

Frequencies

GnomAD3 genomes
AF:
0.000165
AC:
11
AN:
66638
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
8246
show subpopulations
Gnomad AFR
AF:
0.000106
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000191
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000230
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000405
AC:
38
AN:
937296
Hom.:
0
Cov.:
40
AF XY:
0.0000102
AC XY:
3
AN XY:
295394
show subpopulations
Gnomad4 AFR exome
AF:
0.0000421
Gnomad4 AMR exome
AF:
0.0000773
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000352
Gnomad4 SAS exome
AF:
0.0000663
Gnomad4 FIN exome
AF:
0.0000276
Gnomad4 NFE exome
AF:
0.0000403
Gnomad4 OTH exome
AF:
0.0000251
GnomAD4 genome
AF:
0.000165
AC:
11
AN:
66625
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
8259
show subpopulations
Gnomad4 AFR
AF:
0.000106
Gnomad4 AMR
AF:
0.000191
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000230
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 18, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 3 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1
Aug 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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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: rs1206863775; hg19: chrX-66765158; API