chr8-144513108-CAT-C

Variant names:

Variant summary

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

The NM_004260.4(RECQL4):c.2492_2493delAT(p.His831ArgfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,568,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 2.40

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:

ENSG00000265393 (HGNC:):

ENSG00000265393 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 8-144513108-CAT-C is Pathogenic according to our data. Variant chr8-144513108-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513108-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.2492_2493delAT	p.His831ArgfsTer52	frameshift_variant	Exon 15 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 link	c.2492_2493delAT	p.His831ArgfsTer52	frameshift_variant	Exon 15 of 21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 link	c.1421_1422delAT	p.His474ArgfsTer52	frameshift_variant	Exon 14 of 20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 link	c.662_663delAT	p.His221fs	frameshift_variant	Exon 6 of 8	5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 link	n.271+272_271+273delAT		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151338

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000950

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000769

AC:

AN:

208088

Hom.:

AF XY:

0.0000621

AC XY:

AN XY:

112668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000128

Gnomad ASJ exome

AF:

0.000143

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000751

Gnomad OTH exome

AF:

0.000195

GnomAD4 exome

AF:

0.0000635

AC:

AN:

1417210

Hom.:

AF XY:

0.0000544

AC XY:

AN XY:

699038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000964

Gnomad4 ASJ exome

AF:

0.000170

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.0000375

Gnomad4 FIN exome

AF:

0.0000402

Gnomad4 NFE exome

AF:

0.0000589

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151450

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74000

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000950

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Baller-Gerold syndrome

Pathogenic:2Other:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His831Argfs*52) 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 (rs752729755, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of RECQL4-related conditions (PMID: 10319867, 19291770, 24518840, 28486640). ClinVar contains an entry for this variant (Variation ID: 6064). For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2492_2493del;p.(His831Argfs*52) is a null frameshift variant (NMD) in the RECQL4 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 6064; OMIM: 603780.0003; PMID: 28486640; 24518840; 19291770) - PS4. The variant is present at low allele frequencies population databases (rs752729755 – gnomAD 0.0003304%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(His831Argfs*52) was detected in trans with a pathogenic variant (PMID: 28486640; 24518840; 19291770) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24518840) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided

Pathogenic:2

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 10319867, 24518840, 29478780, 29462647, 19291770, 31604778, 29625052, 31589614, 33294214, 32482547, 33077847, 28486640) -

Inborn genetic diseases

Pathogenic:1

May 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2492_2493delAT (p.H831Rfs*52) alteration, located in exon 15 (coding exon 15) of the RECQL4 gene, consists of a deletion of 2 nucleotides from position 2492 to 2493, causing a translational frameshift with a predicted alternate stop codon after 52 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.2493_2494delAT allele has an overall frequency of 0.007% (17/239426) total alleles studied. The highest observed frequency was 0.0128% (1/23520) of South Asian alleles. This variant has been identified in conjunction with other RECQL4 variants in individuals with features consistent with RECQL4-related disorder; in at least one instance, the variants were identified in trans (Debeljak, 2009; Colombo, 2014; Zhang, 2020; Gutiérrez-Jimeno, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Rapadilino syndrome

Pathogenic:1

Jun 26, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Rothmund-Thomson syndrome type 2

Pathogenic:1

Dec 15, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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