rs5919392

Variant names:

• chrX-67581463-C-T
• rs5919392
• NM_000044.6:c.1616+34701C>T

Variant summary

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

The NM_000044.6(AR):​c.1616+34701C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 111,385 control chromosomes in the GnomAD database, including 79 homozygotes. There are 1,274 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 0.039 (79 hom., 1274 hem., cov: 23)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0500
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1616+34701C>T		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.1616+34701C>T		intron_variant	Intron 1 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 4298 AN: 111333 Hom.: 79 Cov.: 23

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.0661

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.00993

Gnomad SAS AF: 0.0568

Gnomad FIN AF: 0.0732

Gnomad MID AF: 0.0553

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0375

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

GnomAD4 genome AF: 0.0386 AC: 4296 AN: 111385 Hom.: 79 Cov.: 23 AF XY: 0.0379 AC XY: 1274 AN XY: 33659

African (AFR) AF: 0.00717 AC: 221 AN: 30803

American (AMR) AF: 0.0255 AC: 267 AN: 10483

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 216 AN: 2636

East Asian (EAS) AF: 0.00996 AC: 35 AN: 3515

South Asian (SAS) AF: 0.0555 AC: 147 AN: 2650

European-Finnish (FIN) AF: 0.0732 AC: 441 AN: 6024

Middle Eastern (MID) AF: 0.0607 AC: 13 AN: 214

European-Non Finnish (NFE) AF: 0.0540 AC: 2853 AN: 52868

Other (OTH) AF: 0.0384 AC: 58 AN: 1511

Alfa AF: 0.0449 Hom.: 249

Bravo AF: 0.0336

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.96
DANN	Benign	0.59
PhyloP100		-0.050
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: rs5919392; hg19: chrX-66801305;