chr8-144514983-AGGGGC-GGGGG

Variant names:

• chr8-144514983-AGGGGC-GGGGG
• rs1060501383
• NM_004260.4:c.1568_1573delGCCCCTinsCCCCC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004260.4(RECQL4):​c.1568_1573delGCCCCTinsCCCCC​(p.Ser523ThrfsTer35) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S523S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_004260.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.00

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

Our verdict: Pathogenic. The variant received 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 8-144514983-AGGGGC-GGGGG is Pathogenic according to our data. Variant chr8-144514983-AGGGGC-GGGGG is described in ClinVar as [Pathogenic]. Clinvar id is 407029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1568_1573delGCCCCTinsCCCCC	p.Ser523ThrfsTer35	frameshift_variant, missense_variant	Exon 9 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1568_1573delGCCCCTinsCCCCC	p.Ser523ThrfsTer35	frameshift_variant, missense_variant	Exon 9 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.497_502delGCCCCTinsCCCCC	p.Ser166ThrfsTer35	frameshift_variant, missense_variant	Exon 8 of 20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.422_427delGCCCCTinsCCCCC	p.Ser141fs	frameshift_variant, missense_variant	Exon 5 of 9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.591_596delGCCCCTinsCCCCC		non_coding_transcript_exon_variant	Exon 3 of 4

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

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as c.1573delT; 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29642415, 29367366, 27247962, 15964893, 15897384, 12838562, 12734318, 10678659, 18616953) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4: PVS1, PM3, PM2:Supporting -

RECQL4-related disorder Pathogenic:2

Jul 14, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RECQL4 c.1568_1573delinsCCCCC (p.Ser523ThrfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00025 in 276484 control chromosomes (gnomAD). c.1568_1573delinsCCCCC [described in the literature as two variants in cis: c.1568G>C (p.Ser523Thr) and c.1573delT (p.Cys525AlafsX33)] has been reported in multiple individuals affected with RECQL4-Related Disorders (e.g. Siitonen_2009, Suter_2016, Colombo_2018, Salih_2018). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RECQL4 c.1568_1573delinsCCCCC variant is predicted to result in a frameshift and premature protein termination (p.Ser523Thrfs*35). This variant (also denoted as c.1568G>C;c.1573delT) has been reported in the compound heterozygous state in multiple individuals with Rothmund-Thomson syndrome (Suter et al. 2016. PubMed ID: 27247962; Salih et al 2018. PubMed ID: 29367366; Colombo et al. 2018. PubMed ID: 29642415). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in RECQL4 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Rothmund-Thomson syndrome type 2 Pathogenic:1

Jul 15, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RECQL4 c.1568_1573delinsCCCCC (p.Ser523ThrfsTer35) change removes six nucleotides and inserts five nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant, referred to as two variants in cis (c.1568G>C; c.1573delT), has been reported in the compound heterozygous state in individuals with RECQL4-related syndromes (PMID:18716613, 27247962, 29367366, 29642415). In summary, this variant meets criteria to be classified as pathogenic. -

Baller-Gerold syndrome Pathogenic:1

Oct 29, 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.Ser523Thrfs*35) 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 (rs386833845, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund–Thomson syndrome (PMID: 10678659, 12838562, 15897384, 15964893, 18716613, 20113479, 29367366, 31829210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.2886delT. ClinVar contains an entry for this variant (Variation ID: 6066). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501383; hg19: chr8-145740367;