rs786200887

chr8-144514489-TGCAGGCC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004260.4(RECQL4):c.1650_1656del(p.Ala551TyrfsTer5) variant causes a frameshift change. 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. A550A) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.71

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 12 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 8-144514489-TGCAGGCC-T is Pathogenic according to our data. Variant chr8-144514489-TGCAGGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 6062.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144514489-TGCAGGCC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1650_1656del	p.Ala551TyrfsTer5	frameshift_variant	10/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1650_1656del	p.Ala551TyrfsTer5	frameshift_variant	10/21	1	NM_004260.4	P1

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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1999

- -

Baller-Gerold syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6062). This variant is also known as 1650del7. This premature translational stop signal has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 10319867). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala551Tyrfs*5) 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). -

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: rs786200887; hg19: chr8-145739873;