1-46261204-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003579.4(RAD54L):c.767-57G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,340,506 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (27 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (18 hom.)
• Consequence: RAD54L NM_003579.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.916

Genes affected

RAD54L (HGNC:9826): (RAD54 like) The protein encoded by this gene belongs to the DEAD-like helicase superfamily, and shares similarity with Saccharomyces cerevisiae Rad54, a protein known to be involved in the homologous recombination and repair of DNA. This protein has been shown to play a role in homologous recombination related repair of DNA double-strand breaks. The binding of this protein to double-strand DNA induces a DNA topological change, which is thought to facilitate homologous DNA paring, and stimulate DNA recombination. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, Dec 2008]

LRRC41 (HGNC:16917): (leucine rich repeat containing 41) Predicted to enable identical protein binding activity. Predicted to be involved in protein ubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-46261204-G-T is Benign according to our data. Variant chr1-46261204-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1679090.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00942 (1305/138476) while in subpopulation AFR AF= 0.0306 (1131/36910). AF 95% confidence interval is 0.0292. There are 27 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD54L	NM_003579.4	c.767-57G>T		intron_variant		ENST00000371975.9
RAD54L	NM_001142548.2	c.767-57G>T		intron_variant
RAD54L	NM_001370766.1	c.227-57G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD54L	ENST00000371975.9	c.767-57G>T		intron_variant		1	NM_003579.4	P1

Frequencies

GnomAD3 genomes AF: 0.00940 AC: 1302 AN: 138460 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00310

Gnomad ASJ AF: 0.00943

Gnomad EAS AF: 0.000841

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0203

Gnomad NFE AF: 0.000438

Gnomad OTH AF: 0.00579

GnomAD4 exome AF: 0.00163 AC: 1965 AN: 1202030 Hom.: 18 Cov.: 30 AF XY: 0.00189 AC XY: 1143 AN XY: 603614

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00653

Gnomad4 EAS exome AF: 0.00153

Gnomad4 SAS exome AF: 0.00908

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00942 AC: 1305 AN: 138476 Hom.: 27 Cov.: 31 AF XY: 0.00943 AC XY: 633 AN XY: 67110

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00310

Gnomad4 ASJ AF: 0.00943

Gnomad4 EAS AF: 0.000843

Gnomad4 SAS AF: 0.0119

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000438

Gnomad4 OTH AF: 0.00576

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.54
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61239976; hg19: chr1-46726876; COSMIC: COSV64336230; COSMIC: COSV64336230;