rs200941778

chr8-144515368-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004260.4(RECQL4):c.1348G>A(p.Val450Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.249

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0088098645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1348G>A	p.Val450Met	missense_variant	7/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1348G>A	p.Val450Met	missense_variant	7/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.277G>A	p.Val93Met	missense_variant	6/20	1
RECQL4	ENST00000532846.2	c.235G>A	p.Val79Met	missense_variant	3/9	5
RECQL4	ENST00000688394.1	n.371G>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000291 AC: 72 AN: 247666 Hom.: 0 AF XY: 0.000215 AC XY: 29 AN XY: 134878

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1460374 Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 96 AN XY: 726460

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152344 Hom.: 0 Cov.: 34 AF XY: 0.000725 AC XY: 54 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000202 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000182 AC: 22

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Rothmund-Thomson syndrome type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 17, 2022

The RECQL4 c.1348G>A (p.Val450Met) missense change has a maximum non-founder subpopulation frequency of 0.099% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect on protein function, but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with RECQL4-associated disorders. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Mar 13, 2022

- -

RECQL4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The RECQL4 c.1348G>A variant is predicted to result in the amino acid substitution p.Val450Met. This variant has been reported in a cohort of individuals presenting with pancreatic ductal adenocarcinoma (Appendix Table 2, Hu et al. 2020. PubMed ID: 32659497) and in a general cohort of patients with a history of cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/239695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	2.1
Dann	Benign	0.47
DEOGEN2	Benign	0.015	T;T
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0088	T;T
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.17	T;T
Polyphen		0.57	.;P
Vest4		0.24
MVP		0.51
GERP RS		-0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200941778; hg19: chr8-145740752;