NM_000044.6:c.1379_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1379_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000044.6(AR):​c.1379_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly460_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 0.0000769 in 559,316 control chromosomes in the GnomAD database, including 7 homozygotes. There are 14 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G460G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., 3 hem., cov: 0)
  • Exomes 𝑓: 0.000082 (7 hom. 11 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 6 publications found

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]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High Hemizygotes in GnomAd4 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
AR	NM_000044.6	c.1379_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly460_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1379_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly460_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0000482 AC: 4 AN: 83058 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000384

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000819 AC: 39 AN: 476258 Hom.: 7 AF XY: 0.0000930 AC XY: 11 AN XY: 118246

African (AFR) AF: 0.0000756 AC: 1 AN: 13219

American (AMR) AF: 0.000582 AC: 5 AN: 8585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9546

East Asian (EAS) AF: 0.0000709 AC: 1 AN: 14099

South Asian (SAS) AF: 0.000815 AC: 12 AN: 14720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21867

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1305

European-Non Finnish (NFE) AF: 0.0000510 AC: 19 AN: 372313

Other (OTH) AF: 0.0000485 AC: 1 AN: 20604

GnomAD4 genome AF: 0.0000482 AC: 4 AN: 83058 Hom.: 0 Cov.: 0 AF XY: 0.000180 AC XY: 3 AN XY: 16622

African (AFR) AF: 0.0000462 AC: 1 AN: 21639

American (AMR) AF: 0.000384 AC: 3 AN: 7805

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2222

East Asian (EAS) AF: 0.00 AC: 0 AN: 2575

South Asian (SAS) AF: 0.00 AC: 0 AN: 1527

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 195

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 43140

Other (OTH) AF: 0.00 AC: 0 AN: 1060

Alfa AF: 0.00 Hom.: 327

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356;