rs199543866

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001413023.1(RECQL4):c.-764C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

RECQL4
NM_001413023.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: -1.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023060977).

BP6

Variant 8-144517096-G-A is Benign according to our data. Variant chr8-144517096-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239755.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.308C>T	p.Pro103Leu	missense_variant	Exon 4 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6 link	c.308C>T	p.Pro103Leu	missense_variant	Exon 4 of 21	1	NM_004260.4	ENSP00000482313.2		O94761

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000604

AC:

149

AN:

246720

Hom.:

AF XY:

0.000572

AC XY:

AN XY:

134654

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000834

GnomAD4 exome

AF:

0.00119

AC:

1735

AN:

1460058

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

810

AN XY:

726302

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152268

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000555

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000909

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000714

AC:

ExAC

AF:

0.000614

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jun 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified without a second RECQL4 variant in a patient with clinical features of Rothmund-Thomson syndrome and with a missense RECQL4 variant in a patient with complex craniosynostosis (PMID: 12734318, 32139749); Observed heterozygous in a patient with sporadic pancreatic cancer and with a second RECQL4 variant in a patient with osteosarcoma (PMID: 32659497, 32191290); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30680959, 32139749, 32659497, 37731390, 35591945, 12734318, 32191290) -

Oct 20, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baller-Gerold syndrome

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Oct 14, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.308C>T, in exon 4 that results in an amino acid change, p.Pro103Leu. This sequence change has been previously described in an individual with RECQL4-related disorder (PMID: 12734318). This sequence change has been described in the gnomAD database with a low frequency of 0.11% in the non-Finnish European subpopulation (dbSNP rs199543866). The p.Pro103Leu change affects a poorly conserved amino acid residue of the RECQL4 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD) provide contradictory results for the p.Pro103Leu substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Pro103Leu change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

May 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308C>T (p.P103L) alteration is located in exon 4 (coding exon 4) of the RECQL4 gene. This alteration results from a C to T substitution at nucleotide position 308, causing the proline (P) at amino acid position 103 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Rothmund-Thomson syndrome type 2

Uncertain:1

Aug 09, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RECQL4 c.308C>T (p.Pro103Leu) missense change has a maximum subpopulation frequency of 0.12% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual meeting diagnostic criteria for Rothmund-Thomson syndrome who did not have a second pathogenic variant in RECQL4 identified (PMID: 12734318). 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

Benign:1

Dec 22, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.4

DANN

Benign

0.86

DEOGEN2

Benign

0.053

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.70

M_CAP

Benign

0.0028

MetaRNN

Benign

0.023

PrimateAI

Benign

0.33

Sift4G

Benign

0.16

Polyphen

0.75

Vest4

0.10

MVP

0.75

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.19

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