1-46267540-GGA-CGG

Variant names:

• chr1-46267540-GGA-CGG
• NM_003579.4:c.973_975delGGAinsCGG
• RAD54L p.Gly325Arg

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_003579.4(RAD54L):​c.973_975delGGAinsCGG​(p.Gly325Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.65
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_003579.4 (RAD54L) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.973_975delGGAinsCGG	p.Gly325Arg	missense	N/A	NP_003570.2	Q92698
	RAD54L	NM_001142548.2		c.973_975delGGAinsCGG	p.Gly325Arg	missense	N/A	NP_001136020.1	Q92698
	RAD54L	NM_001370766.1		c.433_435delGGAinsCGG	p.Gly145Arg	missense	N/A	NP_001357695.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L	ENST00000371975.9	TSL:1 MANE Select	c.973_975delGGAinsCGG	p.Gly325Arg	missense	N/A	ENSP00000361043.4	Q92698
	RAD54L	ENST00000932547.1		c.973_975delGGAinsCGG	p.Gly325Arg	missense	N/A	ENSP00000602606.1
	RAD54L	ENST00000442598.5	TSL:2	c.973_975delGGAinsCGG	p.Gly325Arg	missense	N/A	ENSP00000396113.1	Q92698

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-46733212;