rs754735053

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_004260.4(RECQL4):c.1568G>C(p.Ser523Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,611,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.00

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_004260.4

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 8-144514988-C-G is Benign according to our data. Variant chr8-144514988-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.1568G>C	p.Ser523Thr	missense_variant	9/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.1568G>C	p.Ser523Thr	missense_variant	9/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.497G>C	p.Ser166Thr	missense_variant	8/20	1
RECQL4	ENST00000532846.2 linkuse as main transcript	c.425G>C	p.Ser142Thr	missense_variant	5/9	5
RECQL4	ENST00000688394.1 linkuse as main transcript	n.591G>C		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000246

AC:

AN:

244018

Hom.:

AF XY:

0.000240

AC XY:

AN XY:

133330

show subpopulations

Gnomad AFR exome

AF:

0.0000675

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000427

Gnomad OTH exome

AF:

0.000505

GnomAD4 exome

AF:

0.000410

AC:

599

AN:

1459330

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

294

AN XY:

725822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000385

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000328

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000506

ExAC

AF:

0.000232

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000655

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

The c.1568G>C (p.S523T) alteration is located in exon 9 (coding exon 9) of the RECQL4 gene. This alteration results from a G to C substitution at nucleotide position 1568, causing the serine (S) at amino acid position 523 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Rothmund-Thomson syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 19, 2020

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jul 30, 2021

- -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 523 of the RECQL4 protein (p.Ser523Thr). This variant is present in population databases (rs754735053, gnomAD 0.05%). This missense change has been observed in cis with c.1573del (p.Cys525Alafs*33) in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund‚ÄìThomson syndrome (PMID: 12838562, 15964893, 27247962, 29367366, 29642415). This variant has not been reported in isolation in the literature in individuals affected with RECQL4-related conditions. This variant is also known as g.2881G>C. ClinVar contains an entry for this variant (Variation ID: 259258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RECQL4 protein function with a negative 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

RECQL4: BP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Benign

0.75

DEOGEN2

Benign

0.032

T;T

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0069

MetaRNN

Uncertain

0.47

T;T

PrimateAI

Benign

0.39

Sift4G

Benign

0.096

T;D

Polyphen

0.64

.;P

Vest4

0.81

MVP

0.79

GERP RS

4.6

Varity_R

0.22

gMVP

0.56

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