rs1926926

Variant names:

• chrX-67607731-C-T
• rs1926926
• NM_000044.6:c.1617-35525C>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.1617-35525C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 111,881 control chromosomes in the GnomAD database, including 699 homozygotes. There are 2,175 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 0.071 (699 hom., 2175 hem., cov: 23)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.886
• Publications: 2 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 = 0.24 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1617-35525C>T		intron	N/A	NP_000035.2
	AR	NM_001348063.1		c.1617-35525C>T		intron	N/A	NP_001334992.1
	AR	NM_001348061.1		c.1617-35525C>T		intron	N/A	NP_001334990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1617-35525C>T		intron	N/A	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.1617-35525C>T		intron	N/A	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.1617-35525C>T		intron	N/A	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.0706 AC: 7895 AN: 111826 Hom.: 698 Cov.: 23

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0297

Gnomad NFE AF: 0.000770

Gnomad OTH AF: 0.0575

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

GnomAD4 genome AF: 0.0708 AC: 7925 AN: 111881 Hom.: 699 Cov.: 23 AF XY: 0.0638 AC XY: 2175 AN XY: 34085

African (AFR) AF: 0.245 AC: 7503 AN: 30644

American (AMR) AF: 0.0270 AC: 287 AN: 10623

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

Middle Eastern (MID) AF: 0.0326 AC: 7 AN: 215

European-Non Finnish (NFE) AF: 0.000751 AC: 40 AN: 53229

Other (OTH) AF: 0.0568 AC: 86 AN: 1514

Alfa AF: 0.0353 Hom.: 936

Bravo AF: 0.0810

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.67
DANN	Benign	0.53
PhyloP100		-0.89
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: rs1926926; hg19: chrX-66827573;