X-67698249-T-C

Variant names:

• chrX-67698249-T-C
• rs12011793
• NM_000044.6:c.1885+12123T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000044.6(AR):​c.1885+12123T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 111,734 control chromosomes in the GnomAD database, including 1,373 homozygotes. There are 4,384 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1373 hom., 4384 hem., cov: 23)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• Publications: 1 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1885+12123T>C		intron_variant	Intron 3 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.289+12123T>C		intron_variant	Intron 4 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1885+12123T>C		intron_variant	Intron 3 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.1885+12123T>C		intron_variant	Intron 3 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*233+12123T>C		intron_variant	Intron 4 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.1885+12123T>C		intron_variant	Intron 3 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes AF: 0.142 AC: 15906 AN: 111684 Hom.: 1369 Cov.: 23

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0189

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0624

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0815

Gnomad OTH AF: 0.150

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

GnomAD4 genome AF: 0.143 AC: 15940 AN: 111734 Hom.: 1373 Cov.: 23 AF XY: 0.129 AC XY: 4384 AN XY: 33980

African (AFR) AF: 0.322 AC: 9857 AN: 30592

American (AMR) AF: 0.0880 AC: 934 AN: 10611

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 165 AN: 2643

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3534

South Asian (SAS) AF: 0.0241 AC: 65 AN: 2695

European-Finnish (FIN) AF: 0.0532 AC: 326 AN: 6126

Middle Eastern (MID) AF: 0.120 AC: 26 AN: 216

European-Non Finnish (NFE) AF: 0.0814 AC: 4326 AN: 53113

Other (OTH) AF: 0.149 AC: 226 AN: 1517

Alfa AF: 0.101 Hom.: 5465

Bravo AF: 0.154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		0.30
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: rs12011793; hg19: chrX-66918091;