rs386833844

Positions:

• chr8-144515236-G-A
• chr8-144515236-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001413043.1(RECQL4):​c.-71C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000277 in 1,589,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: RECQL4 NM_001413043.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.04

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• PP5: Variant 8-144515236-G-A is Pathogenic according to our data. Variant chr8-144515236-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144515236-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1397C>T	p.Pro466Leu	missense_variant	8/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1397C>T	p.Pro466Leu	missense_variant	8/21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.326C>T	p.Pro109Leu	missense_variant	7/20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.281C>T	p.Pro94Leu	missense_variant	4/9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.420C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000237 AC: 5 AN: 210890 Hom.: 0 AF XY: 0.0000262 AC XY: 3 AN XY: 114480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000285 AC: 41 AN: 1437156 Hom.: 0 Cov.: 33 AF XY: 0.0000309 AC XY: 22 AN XY: 712906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000489

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000300

Gnomad4 OTH exome AF: 0.0000672

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	The P466L variant in the RECQL4 gene has been reported previously in one individual with Rothmund-Thomson syndrome, and in one individual with RAPADALINO syndrome; both of these individuals harbored a frameshift RECQL4 variant in trans with P466L (Jin et al., 2008; Siitonen et al., 2009). Functional studies demonstrate that the P466L variant results in decreased protein activity as compared to wild type (Jensen et al., 2012). The P466L variant is observed in 4/106770 (0.004%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The P466L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P466L as a likely pathogenic variant. -

Baller-Gerold syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 466 of the RECQL4 protein (p.Pro466Leu). This variant is present in population databases (rs386833844, gnomAD 0.004%). This missense change has been observed in individual(s) with Rothmand-Thompson syndrome (RTS) (PMID: 18504617, 18716613). 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: 56399). 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 expected to disrupt RECQL4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RECQL4 function (PMID: 23238538, 33046774). For these reasons, this variant has been classified as Pathogenic. -

Rapadilino syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	23
DANN	Benign	0.71
DEOGEN2	Benign	0.099	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.83	D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	.;D
Vest4		0.85
MVP		0.80
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs386833844; hg19: chr8-145740620;