rs2361634

Variant names:

• chrX-67643001-A-G
• rs2361634
• NM_000044.6:c.1617-255A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000044.6(AR):​c.1617-255A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 111,642 control chromosomes in the GnomAD database, including 125 homozygotes. There are 1,311 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.043 (125 hom., 1311 hem., cov: 23)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.329
• Publications: 15 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, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-67643001-A-G is Benign according to our data. Variant chrX-67643001-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1617-255A>G		intron_variant	Intron 1 of 7	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1617-255A>G		intron_variant	Intron 1 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 4778 AN: 111588 Hom.: 126 Cov.: 23

Gnomad AFR AF: 0.00921

Gnomad AMI AF: 0.0886

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0710

Gnomad OTH AF: 0.0207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0427 AC: 4772 AN: 111642 Hom.: 125 Cov.: 23 AF XY: 0.0387 AC XY: 1311 AN XY: 33854

African (AFR) AF: 0.00919 AC: 283 AN: 30780

American (AMR) AF: 0.0221 AC: 232 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 63 AN: 2646

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3520

South Asian (SAS) AF: 0.0232 AC: 62 AN: 2672

European-Finnish (FIN) AF: 0.0445 AC: 269 AN: 6045

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.0710 AC: 3768 AN: 53074

Other (OTH) AF: 0.0205 AC: 31 AN: 1515

Alfa AF: 0.0556 Hom.: 827

Bravo AF: 0.0384

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.35
DANN	Benign	0.56
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2361634; hg19: chrX-66862843;