rs36023964

chr8-144512437-G-Achr8-144512437-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_004260.4(RECQL4):c.3010C>T(p.Arg1004Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,610,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1004Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 3.00

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 Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012914628).
• BP6: Variant 8-144512437-G-A is Benign according to our data. Variant chr8-144512437-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.3010C>T	p.Arg1004Trp	missense_variant	17/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.3010C>T	p.Arg1004Trp	missense_variant	17/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000290 AC: 71 AN: 244556 Hom.: 0 AF XY: 0.000232 AC XY: 31 AN XY: 133740

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000394

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1457790 Hom.: 0 Cov.: 68 AF XY: 0.000155 AC XY: 112 AN XY: 724834

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152338 Hom.: 0 Cov.: 34 AF XY: 0.000940 AC XY: 70 AN XY: 74494

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.00259 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000358 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	See Variant Classification Assertion Criteria. -

Rothmund-Thomson syndrome type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 12, 2020

- -

Baller-Gerold syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

RECQL4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Benign	0.87
DEOGEN2	Benign	0.11	T;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.013	T;T;T
PrimateAI	Benign	0.34	T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.55
MVP		0.77
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.25
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs36023964; hg19: chr8-145737820; COSMIC: COSV56743959; COSMIC: COSV56743959;