chrX-67545316-TGCAGCAGCA-T

Variant names:

• chrX-67545316-TGCAGCAGCA-T
• rs3032358
• NM_000044.6:c.231_239delGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_000044.6(AR):​c.231_239delGCAGCAGCA​(p.Gln78_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 0.0287 in 982,901 control chromosomes in the GnomAD database, including 418 homozygotes. There are 3,243 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (308 hom., 647 hem., cov: 0)
  • Exomes 𝑓: 0.024 (110 hom. 2596 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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-TGCAGCAGCA-T is Benign according to our data. Variant chrX-67545316-TGCAGCAGCA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.231_239delGCAGCAGCA	p.Gln78_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.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.231_239delGCAGCAGCA	p.Gln78_Gln80del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 6492 AN: 66530 Hom.: 308 Cov.: 0

Gnomad AFR AF: 0.0956

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0921

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.0670

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0961

GnomAD4 exome AF: 0.0237 AC: 21760 AN: 916384 Hom.: 110 AF XY: 0.00938 AC XY: 2596 AN XY: 276646

African (AFR) AF: 0.0319 AC: 746 AN: 23351

American (AMR) AF: 0.0250 AC: 636 AN: 25439

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 743 AN: 15703

East Asian (EAS) AF: 0.0320 AC: 887 AN: 27742

South Asian (SAS) AF: 0.0176 AC: 747 AN: 42325

European-Finnish (FIN) AF: 0.0468 AC: 1634 AN: 34883

Middle Eastern (MID) AF: 0.0398 AC: 100 AN: 2511

European-Non Finnish (NFE) AF: 0.0212 AC: 14931 AN: 705568

Other (OTH) AF: 0.0344 AC: 1336 AN: 38862

GnomAD4 genome AF: 0.0976 AC: 6493 AN: 66517 Hom.: 308 Cov.: 0 AF XY: 0.0788 AC XY: 647 AN XY: 8215

African (AFR) AF: 0.0957 AC: 1796 AN: 18771

American (AMR) AF: 0.0731 AC: 382 AN: 5227

Ashkenazi Jewish (ASJ) AF: 0.0921 AC: 158 AN: 1715

East Asian (EAS) AF: 0.0391 AC: 72 AN: 1841

South Asian (SAS) AF: 0.0667 AC: 60 AN: 900

European-Finnish (FIN) AF: 0.0659 AC: 133 AN: 2019

Middle Eastern (MID) AF: 0.135 AC: 18 AN: 133

European-Non Finnish (NFE) AF: 0.108 AC: 3744 AN: 34658

Other (OTH) AF: 0.0949 AC: 77 AN: 811

Alfa AF: 0.0457 Hom.: 237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=200/0	polymorphism (auto)

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: COSV65958085;