X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

Position:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

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.1403_1420del​(p.Gly468_Gly473del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 558,345 control chromosomes in the GnomAD database, including 1,198 homozygotes. There are 3,999 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G457G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., 172 hem., cov: 0)
  • Exomes 𝑓: 0.028 (1191 hom. 3827 hem.)
• Consequence: AR NM_000044.6 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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-TGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1168910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0276 (13127/475300) while in subpopulation SAS AF= 0.0455 (667/14650). AF 95% confidence interval is 0.0427. There are 1191 homozygotes in gnomad4_exome. There are 3827 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1403_1420del	p.Gly468_Gly473del	inframe_deletion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1403_1420del	p.Gly468_Gly473del	inframe_deletion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 912 AN: 83041 Hom.: 7 Cov.: 0 AF XY: 0.0104 AC XY: 172 AN XY: 16605

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.00666

Gnomad ASJ AF: 0.00945

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00672

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00660

GnomAD3 exomes AF: 0.0287 AC: 1079 AN: 37570 Hom.: 294 AF XY: 0.0225 AC XY: 292 AN XY: 12980

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.0447

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.0256

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.00673

Gnomad NFE exome AF: 0.0376

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0276 AC: 13127 AN: 475300 Hom.: 1191 AF XY: 0.0325 AC XY: 3827 AN XY: 117708

Gnomad4 AFR exome AF: 0.00793

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.00633

Gnomad4 SAS exome AF: 0.0455

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.0110 AC: 912 AN: 83045 Hom.: 7 Cov.: 0 AF XY: 0.0104 AC XY: 172 AN XY: 16615

Gnomad4 AFR AF: 0.00499

Gnomad4 AMR AF: 0.00665

Gnomad4 ASJ AF: 0.00945

Gnomad4 EAS AF: 0.00273

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00672

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.00651

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

AR: BS1, BS2 -

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;