chr8-144514983-AGGGGC-GGGGG

Position:

• chr8-144514983-AGGGGC-GGGGG

Variant summary

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

The ENST00000617875.6(RECQL4):​c.1568_1573delGCCCCTinsCCCCC​(p.Ser523fs) 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 ENST00000617875.6 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

RECQL4 (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 8-144514983-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/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1568_1573delGCCCCTinsCCCCC	p.Ser523fs	frameshift_variant, missense_variant	9/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1568_1573delGCCCCTinsCCCCC	p.Ser523fs	frameshift_variant, missense_variant	9/21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.497_502delGCCCCTinsCCCCC	p.Ser166fs	frameshift_variant, missense_variant	8/20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.422_427delGCCCCTinsCCCCC	p.Ser141fs	frameshift_variant, missense_variant	5/9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.591_596delGCCCCTinsCCCCC		non_coding_transcript_exon_variant	3/4

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RECQL4: PVS1, PM2, PS4:Moderate, BP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	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) -

RECQL4-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2021	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. -

Computational scores

Source: dbNSFP v4.3

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;