rs200941778
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_004260.4(RECQL4):c.1348G>A(p.Val450Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004260.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RECQL4 | NM_004260.4 | c.1348G>A | p.Val450Met | missense_variant | 7/21 | ENST00000617875.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RECQL4 | ENST00000617875.6 | c.1348G>A | p.Val450Met | missense_variant | 7/21 | 1 | NM_004260.4 | P1 | |
RECQL4 | ENST00000621189.4 | c.277G>A | p.Val93Met | missense_variant | 6/20 | 1 | |||
RECQL4 | ENST00000532846.2 | c.235G>A | p.Val79Met | missense_variant | 3/9 | 5 | |||
RECQL4 | ENST00000688394.1 | n.371G>A | non_coding_transcript_exon_variant | 1/4 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152226Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000291 AC: 72AN: 247666Hom.: 0 AF XY: 0.000215 AC XY: 29AN XY: 134878
GnomAD4 exome AF: 0.000128 AC: 187AN: 1460374Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 96AN XY: 726460
GnomAD4 genome ? AF: 0.000571 AC: 87AN: 152344Hom.: 0 Cov.: 34 AF XY: 0.000725 AC XY: 54AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Rothmund-Thomson syndrome type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 17, 2022 | The RECQL4 c.1348G>A (p.Val450Met) missense change has a maximum non-founder subpopulation frequency of 0.099% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect on protein function, but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with RECQL4-associated disorders. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
RECQL4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 06, 2024 | The RECQL4 c.1348G>A variant is predicted to result in the amino acid substitution p.Val450Met. This variant has been reported in a cohort of individuals presenting with pancreatic ductal adenocarcinoma (Appendix Table 2, Hu et al. 2020. PubMed ID: 32659497) and in a general cohort of patients with a history of cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/239695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 13, 2022 | - - |
Baller-Gerold syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at