X-67546514-T-TGGCGGCGGCGGC

Position:

• chrX-67546514-T-TGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000044.6(AR):​c.1409_1420dup​(p.Gly470_Gly473dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G456G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., 59 hem., cov: 0)
  • Exomes 𝑓: 0.0014 (5 hom. 208 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00672 (558/83059) while in subpopulation AFR AF= 0.0199 (432/21655). AF 95% confidence interval is 0.0184. There are 6 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.1409_1420dup	p.Gly470_Gly473dup	inframe_insertion	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.1409_1420dup	p.Gly470_Gly473dup	inframe_insertion	1/8	1	NM_000044.6	P1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 558 AN: 83055 Hom.: 6 Cov.: 0 AF XY: 0.00355 AC XY: 59 AN XY: 16621

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00405

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.00196

Gnomad FIN AF: 0.000420

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00660

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00138 AC: 657 AN: 476223 Hom.: 5 Cov.: 25 AF XY: 0.00176 AC XY: 208 AN XY: 118245

Gnomad4 AFR exome AF: 0.00923

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000314

Gnomad4 EAS exome AF: 0.000284

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.0000457

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00672 AC: 558 AN: 83059 Hom.: 6 Cov.: 0 AF XY: 0.00355 AC XY: 59 AN XY: 16631

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00405

Gnomad4 EAS AF: 0.00195

Gnomad4 SAS AF: 0.00197

Gnomad4 FIN AF: 0.000420

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00651

ClinVar

Not reported in ClinVar

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;