X-67545316-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA-TGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chrX-67545316-TGCAGCAGCAGCAGCAGCA-T
• rs3032358
• NM_000044.6:c.222_239delGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_000044.6(AR):​c.222_239delGCAGCAGCAGCAGCAGCA​(p.Gln75_Gln80del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,001,605 control chromosomes in the GnomAD database, including 38 homozygotes. There are 591 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (35 hom., 185 hem., cov: 0)
  • Exomes 𝑓: 0.0028 (3 hom. 406 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.40
• Publications: 10 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BP6: Variant X-67545316-TGCAGCAGCAGCAGCAGCA-T is Benign according to our data. Variant chrX-67545316-TGCAGCAGCAGCAGCAGCA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 418806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0195 (1300/66602) while in subpopulation AFR AF = 0.0385 (723/18788). AF 95% confidence interval is 0.0362. There are 35 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	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.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.222_239delGCAGCAGCAGCAGCAGCA	p.Gln75_Gln80del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 1299 AN: 66615 Hom.: 35 Cov.: 0

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0134

Gnomad EAS AF: 0.00487

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.0137

GnomAD4 exome AF: 0.00277 AC: 2591 AN: 935003 Hom.: 3 AF XY: 0.00138 AC XY: 406 AN XY: 293243

African (AFR) AF: 0.0135 AC: 317 AN: 23416

American (AMR) AF: 0.00551 AC: 142 AN: 25763

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 104 AN: 16181

East Asian (EAS) AF: 0.00368 AC: 104 AN: 28269

South Asian (SAS) AF: 0.00223 AC: 100 AN: 44784

European-Finnish (FIN) AF: 0.00750 AC: 271 AN: 36130

Middle Eastern (MID) AF: 0.00155 AC: 4 AN: 2579

European-Non Finnish (NFE) AF: 0.00190 AC: 1367 AN: 718132

Other (OTH) AF: 0.00458 AC: 182 AN: 39749

GnomAD4 genome AF: 0.0195 AC: 1300 AN: 66602 Hom.: 35 Cov.: 0 AF XY: 0.0224 AC XY: 185 AN XY: 8248

African (AFR) AF: 0.0385 AC: 723 AN: 18788

American (AMR) AF: 0.0139 AC: 73 AN: 5236

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 23 AN: 1715

East Asian (EAS) AF: 0.00489 AC: 9 AN: 1839

South Asian (SAS) AF: 0.00777 AC: 7 AN: 901

European-Finnish (FIN) AF: 0.0114 AC: 23 AN: 2025

Middle Eastern (MID) AF: 0.00752 AC: 1 AN: 133

European-Non Finnish (NFE) AF: 0.00913 AC: 317 AN: 34710

Other (OTH) AF: 0.0148 AC: 12 AN: 812

Alfa AF: 0.00 Hom.: 237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=191/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3032358; hg19: chrX-66765158; COSMIC: COSV65961770;