Genetic Variant RECQL4:p.Val799Leu (chr8-144513286-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):c.2395G>C(p.Val799Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V799M) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 links:

ENSG00000265393 (HGNC:):

ENSG00000265393 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.2395G>C	p.Val799Leu	missense_variant	Exon 14 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 link	c.2395G>C	p.Val799Leu	missense_variant	Exon 14 of 21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 link	c.1324G>C	p.Val442Leu	missense_variant	Exon 13 of 20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 link	c.633+130G>C		intron_variant	Intron 5 of 7	5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 link	n.272-320C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000887

AC:

AN:

225518

Hom.:

AF XY:

0.00000798

AC XY:

AN XY:

125386

show subpopulations

Gnomad AFR exome

AF:

0.000147

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1446444

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Baller-Gerold syndrome

Uncertain:1

May 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 799 of the RECQL4 protein (p.Val799Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.096

T;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.48

T;T

MutationAssessor

Benign

0.20

.;N

PrimateAI

Uncertain

0.56

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.97

.;D

Vest4

0.58

MVP

0.37

GERP RS

3.9

Varity_R

0.29

gMVP

0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over