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rs1060501370

chr8-144516313-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004260.4(RECQL4):c.805del(p.Trp269GlyfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -1.08
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-144516313-CA-C is Pathogenic according to our data. Variant chr8-144516313-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 406956.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.805del p.Trp269GlyfsTer24 frameshift_variant 5/21 ENST00000617875.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.805del p.Trp269GlyfsTer24 frameshift_variant 5/211 NM_004260.4 P1
RECQL4ENST00000621189.4 linkuse as main transcriptc.-267del 5_prime_UTR_variant 4/201
RECQL4ENST00000524998.1 linkuse as main transcriptc.327del p.Trp110GlyfsTer24 frameshift_variant 3/43
RECQL4ENST00000534538.1 linkuse as main transcriptc.*609del 3_prime_UTR_variant, NMD_transcript_variant 4/43

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000413
AC:
1
AN:
242414
Hom.:
0
AF XY:
0.00000756
AC XY:
1
AN XY:
132292
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000913
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457622
Hom.:
0
Cov.:
66
AF XY:
0.00000138
AC XY:
1
AN XY:
724914
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Baller-Gerold syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 14, 2016For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 1 nucleotide from exon 5 of the RECQL4 mRNA (c.805delT), causing a frameshift at codon 269. This creates a premature translational stop signal (p.Trp269Glyfs*24) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060501370; hg19: chr8-145741697; API