rs386833845

Positions:

chr8-144514982-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000617875.6(RECQL4):c.1573del(p.Cys525AlafsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,611,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C525C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

RECQL4
ENST00000617875.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 0.576

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144514982-CA-C is Pathogenic according to our data. Variant chr8-144514982-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 6066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514982-CA-C is described in Lovd as [Likely_pathogenic]. Variant chr8-144514982-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.1573del	p.Cys525AlafsTer33	frameshift_variant	9/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.1573del	p.Cys525AlafsTer33	frameshift_variant	9/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.502del	p.Cys168AlafsTer33	frameshift_variant	8/20	1		ENSP00000483145
RECQL4	ENST00000532846.2 linkuse as main transcript	c.428del	p.Cys144AlafsTer33	frameshift_variant	5/9	5		ENSP00000476551
RECQL4	ENST00000688394.1 linkuse as main transcript	n.596del		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152168

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:

0.000241

AC:

AN:

245124

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

133808

show subpopulations

Gnomad AFR exome

AF:

0.0000667

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:

0.0000474

Gnomad NFE exome

AF:

0.000416

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.000409

AC:

597

AN:

1459566

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

293

AN XY:

725978

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:

0.0000384

Gnomad4 NFE exome

AF:

0.000494

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74466

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:

0.000108

Hom.:

Bravo

AF:

0.000506

EpiCase

AF:

0.000436

EpiControl

AF:

0.000653

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	RECQL4: PVS1, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31829210, 29367366, 28423363, 12734318, 12838562, 18716613, 15964893, 30947698, 31604778, 29625052, 32081490, 31980526, 31589614, 10678659, 34308104) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Baller-Gerold syndrome

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Cys525Alafs*33) in the RECQL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs386833845, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund‚ÄìThomson syndrome (PMID: 10678659, 12838562, 15897384, 15964893, 18716613, 20113479, 29367366, 31829210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.2886delT. ClinVar contains an entry for this variant (Variation ID: 6066). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -

B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 15, 2016

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

The c.1573delT (p.C525Afs*33) alteration, located in exon 9 (coding exon 9) of the RECQL4 gene, consists of a deletion of one nucleotide at position 1573, causing a translational frameshift with a predicted alternate stop codon after 33 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous and compound heterozygous states in individuals with RECQL4-related disorders with and without malignancies (Van Maldergem, 2006; Siitonen, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

Rapadilino syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

- -

High grade surface osteosarcoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 20, 2016

- -

Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 06, 2022

- -

Rothmund-Thomson syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 23, 2017

- -

Rothmund-Thomson syndrome type 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2006

- -

RECQL4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 09, 2021

Variant summary: RECQL4 c.1573delT (p.Cys525AlafsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by other laboratories (ClinVar). The variant allele was found at a frequency of 0.00024 in 245124 control chromosomes (gnomAD). c.1573delT has been reported in the literature in multiple individuals affected with RECQL4-Related Disorders (e.g. Siitonen_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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