X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGC

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_000044.6(AR):​c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG​(p.Gly462_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 0.00106 in 559,092 control chromosomes in the GnomAD database, including 55 homozygotes. There are 195 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. G462G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 5 hem., cov: 0)
  • Exomes 𝑓: 0.0012 (55 hom. 190 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0012 (572/476032) while in subpopulation SAS AF = 0.00945 (139/14707). AF 95% confidence interval is 0.00817. There are 55 homozygotes in GnomAdExome4. There are 190 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 5 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.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_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.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1385_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly462_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 22 AN: 83056 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000384

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000209

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00120 AC: 572 AN: 476032 Hom.: 55 AF XY: 0.00161 AC XY: 190 AN XY: 118084

African (AFR) AF: 0.000151 AC: 2 AN: 13218

American (AMR) AF: 0.00303 AC: 26 AN: 8578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9545

East Asian (EAS) AF: 0.00241 AC: 34 AN: 14084

South Asian (SAS) AF: 0.00945 AC: 139 AN: 14707

European-Finnish (FIN) AF: 0.000183 AC: 4 AN: 21856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1303

European-Non Finnish (NFE) AF: 0.000938 AC: 349 AN: 372150

Other (OTH) AF: 0.000874 AC: 18 AN: 20591

GnomAD4 genome AF: 0.000265 AC: 22 AN: 83060 Hom.: 0 Cov.: 0 AF XY: 0.000301 AC XY: 5 AN XY: 16632

African (AFR) AF: 0.000185 AC: 4 AN: 21655

American (AMR) AF: 0.000384 AC: 3 AN: 7817

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

East Asian (EAS) AF: 0.00117 AC: 3 AN: 2564

South Asian (SAS) AF: 0.00197 AC: 3 AN: 1520

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: 0.000209 AC: 9 AN: 43137

Other (OTH) AF: 0.00 AC: 0 AN: 1076

Alfa AF: 0.00 Hom.: 327

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen insensitivity, partial, with breast cancer (1)
-	1	-	Androgen resistance syndrome (1)
-	1	-	AR-related disorder (1)
-	1	-	Hypospadias 1, X-linked (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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746853821;

hg19: chrX-66766356;