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rs137853232

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_004260.4(RECQL4):c.3061C>T(p.Arg1021Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,612,194 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1021Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

11

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 0.324
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-144512319-G-A is Pathogenic according to our data. Variant chr8-144512319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.09077656).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.3061C>T p.Arg1021Trp missense_variant 18/21 ENST00000617875.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.3061C>T p.Arg1021Trp missense_variant 18/211 NM_004260.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152258
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000365
AC:
9
AN:
246686
Hom.:
0
AF XY:
0.0000446
AC XY:
6
AN XY:
134642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000167
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000360
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1459818
Hom.:
0
Cov.:
79
AF XY:
0.0000248
AC XY:
18
AN XY:
726148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152376
Hom.:
0
Cov.:
35
AF XY:
0.0000134
AC XY:
1
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000837
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000416
AC:
5

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Baller-Gerold syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2009- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 07, 2023This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1021 of the RECQL4 protein (p.Arg1021Trp). This variant is present in population databases (rs137853232, gnomAD 0.007%). This missense change has been observed in individual(s) with Baller-Gerold syndrome and Rothmund-Thomson syndrome (PMID: 15897384, 15964893, 23899764, 24635570). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RECQL4 protein function. For these reasons, this variant has been classified as Pathogenic. -
RECQL4-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 03, 2024The RECQL4 c.3061C>T variant is predicted to result in the amino acid substitution p.Arg1021Trp. This variant has been reported as causative for Rothmund-Thomson / RAPADILINO syndrome (Kellermayer et al. 2005. PubMed ID: 15897384; Van Maldergem et al. 2005. PubMed ID: 15964893). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.49
Cadd
Benign
14
Dann
Benign
0.71
DEOGEN2
Benign
0.029
T;T;T
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.30
T;T;T
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.091
T;T;T
PrimateAI
Benign
0.32
T
Sift4G
Benign
0.20
T;T;T
Polyphen
0.0010
.;B;.
Vest4
0.14
MVP
0.74
GERP RS
-0.32
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.2
Varity_R
0.30
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: rs137853232; hg19: chr8-145737702; COSMIC: COSV56739350; COSMIC: COSV56739350; API