chr8-144513108-CAT-C

Position:

chr8-144513108-CAT-C

Variant summary

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

The ENST00000617875.6(RECQL4):c.2492_2493del(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 (★★). Synonymous variant affecting the same amino acid position (i.e. H831H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RECQL4
ENST00000617875.6 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:

(HGNC:):

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/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2492_2493del	p.His831ArgfsTer52	frameshift_variant	15/21	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.2492_2493del	p.His831ArgfsTer52	frameshift_variant	15/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1421_1422del	p.His474ArgfsTer52	frameshift_variant	14/20	1		ENSP00000483145
	ENST00000580385.1 linkuse as main transcript	n.271+272_271+273del		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.663_664del	p.His222ArgfsTer52	frameshift_variant	6/8	5		ENSP00000477457

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Aug 10, 2022	The c.2492_2493del;p.(His831Argfs52) 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.(His831Argfs52) 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. -
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.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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 26, 2019

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1998

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Nov 01, 2021

- -

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