8-144514203-G-C

Variant names:

• chr8-144514203-G-C
• rs373717016
• NM_004260.4:c.1864C>G

Variant summary

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

The NM_004260.4(RECQL4):​c.1864C>G​(p.Leu622Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.52

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]

ACMG classification

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	c.1864C>G	p.Leu622Val	missense_variant	Exon 11 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1864C>G	p.Leu622Val	missense_variant	Exon 11 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.793C>G	p.Leu265Val	missense_variant	Exon 10 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.232C>G	p.Leu78Val	missense_variant	Exon 2 of 8	5		ENSP00000477457.1
RECQL4	ENST00000532846.2	c.718C>G	p.Leu240Val	missense_variant	Exon 7 of 9	5		ENSP00000476551.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460110 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726340

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L622V variant (also known as c.1864C>G), located in coding exon 11 of the RECQL4 gene, results from a C to G substitution at nucleotide position 1864. The leucine at codon 622 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Baller-Gerold syndrome Uncertain:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 622 of the RECQL4 protein (p.Leu622Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2080943). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RECQL4 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.44	T;T
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.94	.;P
Vest4		0.58
MVP		0.40
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.41
gMVP		0.55

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: rs373717016; hg19: chr8-145739587;