Genetic Variant RAD54L:p.Val444Glu (chr1-46272758-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_003579.4(RAD54L):c.1331T>A(p.Val444Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAD54L
NM_003579.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.89

Publications

1 publications found

Variant links:

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]

RAD54L links:

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]

LRRC41 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-46272758-T-A is Pathogenic according to our data. Variant chr1-46272758-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6192.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD54L	NM_003579.4 link	c.1331T>A	p.Val444Glu	missense_variant	Exon 12 of 18	ENST00000371975.9	NP_003570.2	Q92698
RAD54L	NM_001142548.2 link	c.1331T>A	p.Val444Glu	missense_variant	Exon 13 of 19		NP_001136020.1	Q92698A8K996
RAD54L	NM_001370766.1 link	c.791T>A	p.Val264Glu	missense_variant	Exon 12 of 18		NP_001357695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD54L	ENST00000371975.9 link	c.1331T>A	p.Val444Glu	missense_variant	Exon 12 of 18	1	NM_003579.4	ENSP00000361043.4		Q92698

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Non-Hodgkin lymphoma

Pathogenic:1

Jun 03, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;.

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.92

L;L

PhyloP100

5.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.81

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.091

B;B

Vest4

0.79

MutPred

0.51

Gain of disorder (P = 0.0539);Gain of disorder (P = 0.0539);

MVP

0.82

MPC

0.26

ClinPred

0.81

GERP RS

5.0

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.58

gMVP

0.71

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: -4

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over