rs137853229

Positions:

chr8-144513412-G-A

Variant summary

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

The NM_004260.4(RECQL4):c.2269C>T(p.Gln757*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,608,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.45

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:

RECQL4 (HGNC:):

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 8-144513412-G-A is Pathogenic according to our data. Variant chr8-144513412-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513412-G-A is described in Lovd as [Pathogenic]. Variant chr8-144513412-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2269C>T	p.Gln757*	stop_gained	14/21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2269C>T	p.Gln757*	stop_gained	14/21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1198C>T	p.Gln400*	stop_gained	13/20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 linkuse as main transcript	c.633+4C>T		splice_region_variant, intron_variant		5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 linkuse as main transcript	n.272-194G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

239722

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

131968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000379

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

178

AN:

1456590

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

724868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

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:

0.000145

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000825

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.0000835

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2022	Nonsense 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: 12734318, 10319867, 25120469, 18716613, 24635570, 21418107, 27247962, 33541411) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RECQL4: PVS1, PM3:Strong, PP1:Strong, PM2 -

Rothmund-Thomson syndrome type 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 24, 2022	The RECQL4 c.2269C>T (p.Gln757Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with Rothmund-Thomson syndrome and RAPADILINO syndrome (PM3_verystrong; PMID: 8737976, 10319867, 21418107, 25120469, 18716613, 18616953, 12734318, 24635570, 27247962). It has also been reported in the heterozygous state in an individual with osteosarcoma (PMID: 31604778). This variant has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-145738796-G-A?dataset=gnomad_r2_1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PM3_verystrong. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2021

The c.2269C>T (p.Q757*) alteration, located in exon 14 (coding exon 14) of the RECQL4 gene, consists of a C to T substitution at nucleotide position 2269. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 757. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the RECQL4 c.2269C>T alteration was observed in 0.01% (32/271122) of total alleles studied, with a frequency of 0.04% (14/35144) in the Latino subpopulation. This recurrent mutation has been reported in the homozygous state and presumed in trans with other truncating alterations in patients with RECQL4-related disorders (Siitonen, 2009; Piard, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Rothmund-Thomson syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

May 02, 2014

- -

Baller-Gerold syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Gln757*) 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 (rs137853229, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with RAPADILINO syndrome and Rothmund-Thomson syndrome (PMID: 10319867, 12734318, 18716613, 21418107, 24635570, 25120469, 27247962). ClinVar contains an entry for this variant (Variation ID: 6063). For these reasons, this variant has been classified as Pathogenic. -

RECQL4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 08, 2021

Variant summary: RECQL4 c.2269C>T (p.Gln757X) 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. The variant allele was found at a frequency of 0.00012 in 239722 control chromosomes (gnomAD). c.2269C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with RECQL4-Related Disorders (e.g. Kitao_1999, Wang_2003, Siitonen_2009). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Benign

0.92

FATHMM_MKL

Pathogenic

0.99

Vest4

0.82

GERP RS

5.7

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