X-67557224-G-A

Variant names:

• chrX-67557224-G-A
• rs12396249
• NM_000044.6:c.1616+10462G>A

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+10462G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 110,501 control chromosomes in the GnomAD database, including 1,844 homozygotes. There are 5,603 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 0.19 (1844 hom., 5603 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• Publications: 10 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 (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1616+10462G>A		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+10462G>A		intron_variant	Intron 1 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.190 AC: 20989 AN: 110447 Hom.: 1848 Cov.: 22

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.190 AC: 20994 AN: 110501 Hom.: 1844 Cov.: 22 AF XY: 0.171 AC XY: 5603 AN XY: 32771

African (AFR) AF: 0.331 AC: 9988 AN: 30185

American (AMR) AF: 0.111 AC: 1157 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 301 AN: 2636

East Asian (EAS) AF: 0.00114 AC: 4 AN: 3503

South Asian (SAS) AF: 0.0811 AC: 210 AN: 2590

European-Finnish (FIN) AF: 0.111 AC: 659 AN: 5927

Middle Eastern (MID) AF: 0.172 AC: 37 AN: 215

European-Non Finnish (NFE) AF: 0.157 AC: 8299 AN: 52824

Other (OTH) AF: 0.172 AC: 258 AN: 1498

Alfa AF: 0.155 Hom.: 5580

Bravo AF: 0.195

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.49
PhyloP100		0.065
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: rs12396249; hg19: chrX-66777066;