rs1060501353

chr8-144515984-TTACC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Very_Strong

The NM_004260.4(RECQL4):c.1131_1131+3del variant causes a splice donor, splice donor region, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q377Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_004260.4 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.88

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.21395092 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 8-144515984-TTACC-T is Pathogenic according to our data. Variant chr8-144515984-TTACC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1131_1131+3del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	5/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1131_1131+3del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	5/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.60_60+3del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	4/20	1
RECQL4	ENST00000524998.1	c.653_653+3del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	3/4	3
RECQL4	ENST00000532846.2	c.16_16+3del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	1/9	5

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Nov 11, 2020

- -

Baller-Gerold syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

This variant results in the deletion of part of exon 5 (c.1131_1131+3) of the RECQL4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 406879). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501353; hg19: chr8-145741368;