chr1-46278228-C-T

Variant names:

• chr1-46278228-C-T
• rs1048771
• NM_003579.4:c.2190C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003579.4(RAD54L):​c.2190C>T​(p.Ala730Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,356 control chromosomes in the GnomAD database, including 17,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1240 hom., cov: 32)
  • Exomes 𝑓: 0.13 (16682 hom.)
• Consequence: RAD54L NM_003579.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.21
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-46278228-C-T is Benign according to our data. Variant chr1-46278228-C-T is described in ClinVar as Benign. ClinVar VariationId is 1678943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003579.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L	NM_003579.4	MANE Select	c.2190C>T	p.Ala730Ala	synonymous	Exon 18 of 18	NP_003570.2	Q92698
	LRRC41	NM_006369.5	MANE Select	c.*637G>A		3_prime_UTR	Exon 10 of 10	NP_006360.3
	RAD54L	NM_001142548.2		c.2190C>T	p.Ala730Ala	synonymous	Exon 19 of 19	NP_001136020.1	Q92698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L	ENST00000371975.9	TSL:1 MANE Select	c.2190C>T	p.Ala730Ala	synonymous	Exon 18 of 18	ENSP00000361043.4	Q92698
	LRRC41	ENST00000617190.5	TSL:1 MANE Select	c.*637G>A		3_prime_UTR	Exon 10 of 10	ENSP00000477792.1	Q15345-2
	RAD54L	ENST00000932547.1		c.2220C>T	p.Ala740Ala	synonymous	Exon 18 of 18	ENSP00000602606.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16389 AN: 151962 Hom.: 1239 Cov.: 32

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0995

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.0848

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.152 AC: 37888 AN: 250040 AF XY: 0.166

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.0962

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.0902

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.132 AC: 193512 AN: 1461276 Hom.: 16682 Cov.: 32 AF XY: 0.140 AC XY: 101963 AN XY: 726888

African (AFR) AF: 0.0427 AC: 1428 AN: 33476

American (AMR) AF: 0.0950 AC: 4242 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3277 AN: 26124

East Asian (EAS) AF: 0.324 AC: 12850 AN: 39672

South Asian (SAS) AF: 0.365 AC: 31407 AN: 86120

European-Finnish (FIN) AF: 0.0938 AC: 5007 AN: 53370

Middle Eastern (MID) AF: 0.218 AC: 1254 AN: 5754

European-Non Finnish (NFE) AF: 0.113 AC: 125804 AN: 1111724

Other (OTH) AF: 0.137 AC: 8243 AN: 60364

GnomAD4 genome AF: 0.108 AC: 16390 AN: 152080 Hom.: 1240 Cov.: 32 AF XY: 0.113 AC XY: 8387 AN XY: 74368

African (AFR) AF: 0.0436 AC: 1811 AN: 41528

American (AMR) AF: 0.0994 AC: 1520 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1579 AN: 5148

South Asian (SAS) AF: 0.372 AC: 1794 AN: 4828

European-Finnish (FIN) AF: 0.0848 AC: 899 AN: 10598

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7892 AN: 67910

Other (OTH) AF: 0.142 AC: 299 AN: 2110

Alfa AF: 0.118 Hom.: 3462

Bravo AF: 0.101

Asia WGS AF: 0.298 AC: 1034 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.125

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	RAD54L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1048771; hg19: chr1-46743900; COSMIC: COSV58441949; COSMIC: COSV58441949;