NM_000044.6:c.237_239dupGCA

Variant names:

• chrX-67545316-T-TGCA
• rs3032358
• NM_000044.6:c.237_239dupGCA

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.237_239dupGCA​(p.Gln80dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 989,447 control chromosomes in the GnomAD database, including 2,419 homozygotes. There are 8,985 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q80Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.081 (446 hom., 389 hem., cov: 0)
  • Exomes 𝑓: 0.036 (1973 hom. 8596 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.337
• 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-T-TGCA is Benign according to our data. Variant chrX-67545316-T-TGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 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.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	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.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.237_239dupGCA	p.Gln80dup	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.0809 AC: 5386 AN: 66566 Hom.: 446 Cov.: 0

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.0968

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0892

Gnomad FIN AF: 0.0822

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0875

Gnomad OTH AF: 0.0773

GnomAD4 exome AF: 0.0364 AC: 33556 AN: 922896 Hom.: 1973 Cov.: 40 AF XY: 0.0304 AC XY: 8596 AN XY: 282430

African (AFR) AF: 0.0257 AC: 606 AN: 23591

American (AMR) AF: 0.0745 AC: 1882 AN: 25247

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 851 AN: 15792

East Asian (EAS) AF: 0.109 AC: 2956 AN: 27130

South Asian (SAS) AF: 0.0664 AC: 2854 AN: 42982

European-Finnish (FIN) AF: 0.0949 AC: 3384 AN: 35673

Middle Eastern (MID) AF: 0.0572 AC: 143 AN: 2502

European-Non Finnish (NFE) AF: 0.0266 AC: 18924 AN: 710836

Other (OTH) AF: 0.0500 AC: 1956 AN: 39143

GnomAD4 genome AF: 0.0809 AC: 5384 AN: 66551 Hom.: 446 Cov.: 0 AF XY: 0.0471 AC XY: 389 AN XY: 8253

African (AFR) AF: 0.0553 AC: 1039 AN: 18777

American (AMR) AF: 0.113 AC: 592 AN: 5223

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 162 AN: 1715

East Asian (EAS) AF: 0.103 AC: 190 AN: 1839

South Asian (SAS) AF: 0.0903 AC: 81 AN: 897

European-Finnish (FIN) AF: 0.0822 AC: 166 AN: 2020

Middle Eastern (MID) AF: 0.105 AC: 14 AN: 133

European-Non Finnish (NFE) AF: 0.0875 AC: 3035 AN: 34691

Other (OTH) AF: 0.0764 AC: 62 AN: 812

Alfa AF: 0.0250 Hom.: 237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=69/31	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: COSV65952534;