X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_000044.6(AR):​c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly463_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 0.000588 in 559,143 control chromosomes in the GnomAD database, including 37 homozygotes. There are 92 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G463G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., 14 hem., cov: 0)
  • Exomes 𝑓: 0.00056 (36 hom. 78 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• 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, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• Kennedy disease

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

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334990.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1388_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly463_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.000746 AC: 62 AN: 83056 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.000900

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000278

Gnomad OTH AF: 0.000943

GnomAD4 exome AF: 0.000559 AC: 266 AN: 476083 Hom.: 36 AF XY: 0.000660 AC XY: 78 AN XY: 118139

African (AFR) AF: 0.00250 AC: 33 AN: 13215

American (AMR) AF: 0.00303 AC: 26 AN: 8582

Ashkenazi Jewish (ASJ) AF: 0.00136 AC: 13 AN: 9541

East Asian (EAS) AF: 0.000355 AC: 5 AN: 14084

South Asian (SAS) AF: 0.00102 AC: 15 AN: 14715

European-Finnish (FIN) AF: 0.0000915 AC: 2 AN: 21851

Middle Eastern (MID) AF: 0.00613 AC: 8 AN: 1306

European-Non Finnish (NFE) AF: 0.000347 AC: 129 AN: 372195

Other (OTH) AF: 0.00170 AC: 35 AN: 20594

GnomAD4 genome AF: 0.000758 AC: 63 AN: 83060 Hom.: 1 Cov.: 0 AF XY: 0.000842 AC XY: 14 AN XY: 16630

African (AFR) AF: 0.00134 AC: 29 AN: 21654

American (AMR) AF: 0.00217 AC: 17 AN: 7817

Ashkenazi Jewish (ASJ) AF: 0.000900 AC: 2 AN: 2222

East Asian (EAS) AF: 0.00 AC: 0 AN: 2563

South Asian (SAS) AF: 0.00131 AC: 2 AN: 1522

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.000278 AC: 12 AN: 43137

Other (OTH) AF: 0.000929 AC: 1 AN: 1076

Alfa AF: 0.00 Hom.: 327

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen resistance syndrome;C1839259:Kennedy disease (1)
-	-	1	AR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=199/1	polymorphism

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; COSMIC: COSV65963038;