8-144512318-C-T

Variant names:

• chr8-144512318-C-T
• rs34666647
• NM_004260.4:c.3062G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004260.4(RECQL4):​c.3062G>A​(p.Arg1021Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,612,274 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0052 (24 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10 O:1
• Conservation: PhyloP100: -0.313

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]

ENSG00000265393 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 8-144512318-C-T is Benign according to our data. Variant chr8-144512318-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=3, not_provided=1}. Variant chr8-144512318-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00411 (627/152382) while in subpopulation NFE AF= 0.00682 (464/68044). AF 95% confidence interval is 0.00631. There are 0 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.3062G>A	p.Arg1021Gln	missense_variant	Exon 18 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.3062G>A	p.Arg1021Gln	missense_variant	Exon 18 of 21	1	NM_004260.4	ENSP00000482313.2

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152264 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00682

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00408 AC: 1006 AN: 246782 Hom.: 1 AF XY: 0.00401 AC XY: 540 AN XY: 134672

Gnomad AFR exome AF: 0.000853

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00516

GnomAD4 exome AF: 0.00523 AC: 7640 AN: 1459892 Hom.: 24 Cov.: 79 AF XY: 0.00512 AC XY: 3716 AN XY: 726186

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00785

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000578

Gnomad4 NFE exome AF: 0.00618

Gnomad4 OTH exome AF: 0.00472

GnomAD4 genome AF: 0.00411 AC: 627 AN: 152382 Hom.: 0 Cov.: 35 AF XY: 0.00389 AC XY: 290 AN XY: 74518

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00682

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00526 Hom.: 0

Bravo AF: 0.00430

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.00769 AC: 65

ExAC AF: 0.00389 AC: 468

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00717

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Jan 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15897384, 30007837, 12734318, 24728327) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4: BP4 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jul 27, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rothmund-Thomson syndrome type 2 Uncertain:1

Oct 16, 2019

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The paternally inherited c.3062G>A variant is a single base pair substitution at nucleotide c.3062 in the exon (19 of 22) of the RECQL4 gene, resulting in the substitution of arginine to glutamine at amino acid position 1021 (1209 in total). This variant is present in the Genome Aggregation Database (gnomAD) with a general frequency of 0.004 (1125/278178, 1 HOMO), indicating it is not a rare variant in the populations represented in this database. This variant is predicted to be tolerated by multiple in silico tools. In Clinvar, this variant has been reported several times with conflicting level of evidence [Benign/Likely Benign/ Variant of Uncertain Significance]. In literature, this R1021Q variant has been observed in a single heterozygous state or with another truncation variant in individual with features of Rothmund-Thomson Syndrome, however this variant has not been established as disease-causing [PMID:12734318;PMID:30007837]. Based on these evidences, the c.3062C>G p.Arg1021Gln variant is classified as Variant of Uncertain Significance (VUS). -

Inborn genetic diseases Benign:1

May 17, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Baller-Gerold syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 25, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.2
DANN	Benign	0.66
DEOGEN2	Benign	0.019	T;T;T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.23	T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0053	T;T;T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.40	.;B;.
Vest4		0.66
MVP		0.72
GERP RS		-4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Varity_R		0.089
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34666647; hg19: chr8-145737701; COSMIC: COSV56740861; COSMIC: COSV56740861;