rs386833843

Positions:

• chr8-144515323-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Moderate

The NM_004260.4(RECQL4):​c.1390+2del variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,612,378 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: RECQL4 NM_004260.4 splice_donor
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.01

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.036118004 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-144515323-CA-C is Pathogenic according to our data. Variant chr8-144515323-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1390+2del		splice_donor_variant		ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1390+2del		splice_donor_variant		1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.319+2del		splice_donor_variant		1
RECQL4	ENST00000532846.2	c.275+2del		splice_donor_variant		5
RECQL4	ENST00000688394.1	n.413+2del		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152250 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000389 AC: 96 AN: 246886 Hom.: 0 AF XY: 0.000424 AC XY: 57 AN XY: 134482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000145 AC: 211 AN: 1460010 Hom.: 1 Cov.: 33 AF XY: 0.000138 AC XY: 100 AN XY: 726222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152368 Hom.: 0 Cov.: 34 AF XY: 0.000617 AC XY: 46 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Rapadilino syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2003	- -

Baller-Gerold syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 12952869, 22885111). Disruption of this splice site has been observed in individual(s) with RAPADILINO syndrome (PMID: 12952869, 18716613). It is commonly reported in individuals of Finnish ancestry (PMID: 12952869, 18716613). Experimental studies have shown that disruption of this splice site affects RECQL4 function (PMID: 17250975, 22885111). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 56398). This variant is also known as IVS7+2delT. This variant is present in population databases (rs386833843, gnomAD 0.4%). This sequence change affects a splice site in intron 7 of the RECQL4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386833843; hg19: chr8-145740707;