NM_000044.6:c.1409_1420dupGCGGCGGCGGCG

Variant names:

• chrX-67546514-T-TGGCGGCGGCGGC
• rs746853821
• NM_000044.6:c.1409_1420dupGCGGCGGCGGCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000044.6(AR):​c.1409_1420dupGCGGCGGCGGCG​(p.Gly470_Gly473dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. E474E) 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 disruptive_inframe_insertion
• 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1409_1420dupGCGGCGGCGGCG	p.Gly470_Gly473dup	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
AR	ENST00000374690.9	c.1409_1420dupGCGGCGGCGGCG	p.Gly470_Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 558 AN: 83055 Hom.: 6 Cov.: 0

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

African (AFR) AF: 0.00923 AC: 122 AN: 13217

American (AMR) AF: 0.00 AC: 0 AN: 8585

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 3 AN: 9550

East Asian (EAS) AF: 0.000284 AC: 4 AN: 14101

South Asian (SAS) AF: 0.00163 AC: 24 AN: 14719

European-Finnish (FIN) AF: 0.0000457 AC: 1 AN: 21872

Middle Eastern (MID) AF: 0.00230 AC: 3 AN: 1305

European-Non Finnish (NFE) AF: 0.00127 AC: 473 AN: 372274

Other (OTH) AF: 0.00131 AC: 27 AN: 20600

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

African (AFR) AF: 0.0199 AC: 432 AN: 21655

American (AMR) AF: 0.00576 AC: 45 AN: 7816

Ashkenazi Jewish (ASJ) AF: 0.00405 AC: 9 AN: 2222

East Asian (EAS) AF: 0.00195 AC: 5 AN: 2564

South Asian (SAS) AF: 0.00197 AC: 3 AN: 1522

European-Finnish (FIN) AF: 0.000420 AC: 1 AN: 2382

Middle Eastern (MID) AF: 0.0115 AC: 2 AN: 174

European-Non Finnish (NFE) AF: 0.00125 AC: 54 AN: 43135

Other (OTH) AF: 0.00651 AC: 7 AN: 1076

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;