X-67544234-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AR	NM_000044.6	c.-913C>A		5_prime_UTR_variant	1/8	ENST00000374690.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AR	ENST00000374690.9	c.-913C>A		5_prime_UTR_variant	1/8	1	NM_000044.6	P1
AR	ENST00000396043.4	c.-913C>A		5_prime_UTR_variant, NMD_transcript_variant	1/9	1
AR	ENST00000612452.5	c.-913C>A		5_prime_UTR_variant, NMD_transcript_variant	1/9	5

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 30 AN: 112074 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34278

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000509

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.000371

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000434

Gnomad4 OTH AF: 0.000656

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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1022210006; hg19: chrX-66764076;