rs1572500

Variant names:

• chrX-67684271-G-T
• rs1572500
• NM_000044.6:c.1769-1739G>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.1769-1739G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 111,517 control chromosomes in the GnomAD database, including 590 homozygotes. There are 1,972 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 0.065 (590 hom., 1972 hem., cov: 23)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.755
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1769-1739G>T		intron_variant	Intron 2 of 7	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1769-1739G>T		intron_variant	Intron 2 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 7236 AN: 111463 Hom.: 590 Cov.: 23

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000749

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0292

Gnomad NFE AF: 0.000791

Gnomad OTH AF: 0.0558

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

GnomAD4 genome AF: 0.0651 AC: 7259 AN: 111517 Hom.: 590 Cov.: 23 AF XY: 0.0584 AC XY: 1972 AN XY: 33739

African (AFR) AF: 0.225 AC: 6869 AN: 30529

American (AMR) AF: 0.0243 AC: 256 AN: 10537

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.0320 AC: 7 AN: 219

European-Non Finnish (NFE) AF: 0.000772 AC: 41 AN: 53087

Other (OTH) AF: 0.0550 AC: 84 AN: 1526

Alfa AF: 0.0566 Hom.: 282

Bravo AF: 0.0748

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.092
DANN	Benign	0.65
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: rs1572500; hg19: chrX-66904113;