X-67544234-C-A

Variant names:

• chrX-67544234-C-A
• rs1022210006
• ENST00000396043.4:n.-913C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000044.6(AR):​c.-913C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 112,110 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.394
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-67544234-C-A is Benign according to our data. Variant chrX-67544234-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660768.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.-913C>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.-913C>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 30 AN: 112074 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000372

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000434

Gnomad OTH AF: 0.000664

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000150 AC: 9 AN: 59894 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16826

African (AFR) AF: 0.00 AC: 0 AN: 2936

American (AMR) AF: 0.000509 AC: 1 AN: 1965

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3518

East Asian (EAS) AF: 0.00 AC: 0 AN: 8592

South Asian (SAS) AF: 0.00 AC: 0 AN: 479

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 249

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 320

European-Non Finnish (NFE) AF: 0.000218 AC: 8 AN: 36724

Other (OTH) AF: 0.00 AC: 0 AN: 5111

GnomAD4 genome AF: 0.000268 AC: 30 AN: 112110 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34324

African (AFR) AF: 0.0000323 AC: 1 AN: 30966

American (AMR) AF: 0.000371 AC: 4 AN: 10770

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3493

South Asian (SAS) AF: 0.00 AC: 0 AN: 2675

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.000434 AC: 23 AN: 53000

Other (OTH) AF: 0.000656 AC: 1 AN: 1524

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000276

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AR: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		-0.39
PromoterAI		-0.051	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1022210006; hg19: chrX-66764076;