rs752729755

Positions:

• chr8-144513108-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004260.4(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 NM_004260.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 2.40

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]

(HGNC:):

ACMG classification

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	UniProt
RECQL4	NM_004260.4	c.2492_2493del	p.His831ArgfsTer52	frameshift_variant	15/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2492_2493del	p.His831ArgfsTer52	frameshift_variant	15/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1421_1422del	p.His474ArgfsTer52	frameshift_variant	14/20	1
	ENST00000580385.1	n.271+272_271+273del		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.663_664del	p.His222ArgfsTer52	frameshift_variant	6/8	5

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151338 Hom.: 0 Cov.: 34

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: 16 AN: 208088 Hom.: 0 AF XY: 0.0000621 AC XY: 7 AN XY: 112668

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: 90 AN: 1417210 Hom.: 0 AF XY: 0.0000544 AC XY: 38 AN XY: 699038

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: 5 AN: 151450 Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 2 AN XY: 74000

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.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baller-Gerold syndrome Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Aug 10, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

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

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

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

Other links and lift over

dbSNP: rs752729755; hg19: chr8-145738491;