NM_000044.6:c.2319-78T>G

Variant names:

• chrX-67721755-T-G
• rs1337076
• NM_000044.6:c.2319-78T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000044.6(AR):​c.2319-78T>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 0.91 (32800 hom., 29722 hem., cov: 22)
  • Exomes 𝑓: 0.99 (355706 hom. 339294 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.963
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-67721755-T-G is Benign according to our data. Variant chrX-67721755-T-G is described in ClinVar as Benign. ClinVar VariationId is 1239857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2319-78T>G		intron_variant	Intron 5 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.723-78T>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.2319-78T>G		intron_variant	Intron 5 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2174-1931T>G		intron_variant	Intron 4 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*667-78T>G		intron_variant	Intron 6 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.2319-78T>G		intron_variant	Intron 5 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.909 AC: 100296 AN: 110307 Hom.: 32807 Cov.: 22

Gnomad AFR AF: 0.685

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.966

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.937

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.990 AC: 1056153 AN: 1066293 Hom.: 355706 AF XY: 0.992 AC XY: 339294 AN XY: 341887

African (AFR) AF: 0.685 AC: 17573 AN: 25651

American (AMR) AF: 0.984 AC: 34547 AN: 35113

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 19162 AN: 19173

East Asian (EAS) AF: 1.00 AC: 30011 AN: 30011

South Asian (SAS) AF: 0.998 AC: 53289 AN: 53373

European-Finnish (FIN) AF: 1.00 AC: 40271 AN: 40271

Middle Eastern (MID) AF: 0.984 AC: 3135 AN: 3187

European-Non Finnish (NFE) AF: 1.00 AC: 814240 AN: 814545

Other (OTH) AF: 0.977 AC: 43925 AN: 44969

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.909 AC: 100332 AN: 110358 Hom.: 32800 Cov.: 22 AF XY: 0.913 AC XY: 29722 AN XY: 32572

African (AFR) AF: 0.685 AC: 20751 AN: 30278

American (AMR) AF: 0.967 AC: 10076 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 2632 AN: 2634

East Asian (EAS) AF: 1.00 AC: 3466 AN: 3466

South Asian (SAS) AF: 0.997 AC: 2490 AN: 2497

European-Finnish (FIN) AF: 1.00 AC: 5846 AN: 5846

Middle Eastern (MID) AF: 0.963 AC: 207 AN: 215

European-Non Finnish (NFE) AF: 0.999 AC: 52776 AN: 52817

Other (OTH) AF: 0.938 AC: 1405 AN: 1498

Alfa AF: 0.938 Hom.: 9775

Bravo AF: 0.897

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

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	-0.95
CADD	Benign	0.61
DANN	Benign	0.36
PhyloP100		-0.96
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: rs1337076; hg19: chrX-66941597;