NM_000044.6:c.2318+243A>G

Variant names:

• chrX-67717865-A-G
• rs5918764
• NM_000044.6:c.2318+243A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000044.6(AR):​c.2318+243A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.82 (27028 hom., 28027 hem., cov: 24)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.760
• Publications: 8 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant X-67717865-A-G is Benign according to our data. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-67717865-A-G is described in CliVar as Benign. Clinvar id is 1183563.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2318+243A>G		intron_variant	Intron 5 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.722+243A>G		intron_variant	Intron 6 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2318+243A>G		intron_variant	Intron 5 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2174-5821A>G		intron_variant	Intron 4 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*666+243A>G		intron_variant	Intron 6 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.2318+243A>G		intron_variant	Intron 5 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.818 AC: 91305 AN: 111618 Hom.: 27034 Cov.: 24

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.931

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.919

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.873

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

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.818 AC: 91338 AN: 111672 Hom.: 27028 Cov.: 24 AF XY: 0.828 AC XY: 28027 AN XY: 33856

African (AFR) AF: 0.524 AC: 16101 AN: 30703

American (AMR) AF: 0.931 AC: 9852 AN: 10579

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 2514 AN: 2645

East Asian (EAS) AF: 0.999 AC: 3516 AN: 3518

South Asian (SAS) AF: 0.944 AC: 2511 AN: 2660

European-Finnish (FIN) AF: 0.937 AC: 5659 AN: 6042

Middle Eastern (MID) AF: 0.916 AC: 196 AN: 214

European-Non Finnish (NFE) AF: 0.923 AC: 49038 AN: 53103

Other (OTH) AF: 0.876 AC: 1337 AN: 1527

Alfa AF: 0.887 Hom.: 17069

Bravo AF: 0.809

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	-1.0
CADD	Benign	0.38
DANN	Benign	0.54
PhyloP100		-0.76
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: rs5918764; hg19: chrX-66937707;