X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000044.6(AR):​c.1415_1420dup​(p.Gly472_Gly473dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G456G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (54 hom., 325 hem., cov: 0)
  • Exomes 𝑓: 0.017 (147 hom. 1890 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-67546514-T-TGGCGGC is Benign according to our data. Variant chrX-67546514-T-TGGCGGC is described in ClinVar as [Likely_benign]. Clinvar id is 434265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0285 (2363/83023) while in subpopulation AFR AF= 0.0457 (989/21636). AF 95% confidence interval is 0.0433. There are 54 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1415_1420dup	p.Gly472_Gly473dup	inframe_insertion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1415_1420dup	p.Gly472_Gly473dup	inframe_insertion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 2360 AN: 83019 Hom.: 54 Cov.: 0 AF XY: 0.0196 AC XY: 325 AN XY: 16609

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0513

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0340

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0170 AC: 8096 AN: 475254 Hom.: 147 Cov.: 25 AF XY: 0.0161 AC XY: 1890 AN XY: 117724

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.000595

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0285 AC: 2363 AN: 83023 Hom.: 54 Cov.: 0 AF XY: 0.0196 AC XY: 325 AN XY: 16619

Gnomad4 AFR AF: 0.0457

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.0164

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0335

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2024	Variant summary: AR c.1415_1420dupGCGGCG (p.Gly472_Gly473dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.019 in 558277 control chromosomes in the gnomAD database, including 201 homozygotes. The observed variant frequency is above the estimated maximal expected allele frequency for a pathogenic variant in AR causing Androgen Resistance Syndrome strongly suggesting that the variant is benign. c.1415_1420dupGCGGCG has been reported in the literature in an individual affected with Androgen Resistance Syndrome (Wu_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29693241). ClinVar contains an entry for this variant (Variation ID: 434265). Based on the evidence outlined above, the variant was classified as benign. -

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

AR: BS1, BS2 -

Androgen resistance syndrome;C0268301:Partial androgen insensitivity syndrome;C0376358:Malignant tumor of prostate;C1839259:Kennedy disease;C2678098:Hypospadias 1, X-linked Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

AR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356;