8-144511967-C-G

Variant names:

• chr8-144511967-C-G
• rs35101495
• NM_004260.4:c.3337G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004260.4(RECQL4):​c.3337G>C​(p.Gly1113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,611,598 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1113A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 0.0940
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037686229).
• BP6: Variant 8-144511967-C-G is Benign according to our data. Variant chr8-144511967-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135152.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00292 (445/152400) while in subpopulation AFR AF = 0.00988 (411/41602). AF 95% confidence interval is 0.00909. There are 0 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.3337G>C	p.Gly1113Arg	missense	Exon 19 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.3412G>C	p.Gly1138Arg	missense	Exon 18 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3337G>C	p.Gly1113Arg	missense	Exon 19 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3337G>C	p.Gly1113Arg	missense	Exon 19 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.2266G>C	p.Gly756Arg	missense	Exon 18 of 20	ENSP00000483145.1
	RECQL4	ENST00000531875.2	TSL:5	c.583G>C	p.Gly195Arg	missense	Exon 4 of 6	ENSP00000477910.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 440 AN: 152282 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000805 AC: 198 AN: 245862 AF XY: 0.000671

Gnomad AFR exome AF: 0.00856

Gnomad AMR exome AF: 0.000990

Gnomad ASJ exome AF: 0.000503

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1459198 Hom.: 4 Cov.: 57 AF XY: 0.000361 AC XY: 262 AN XY: 725948

African (AFR) AF: 0.00899 AC: 301 AN: 33480

American (AMR) AF: 0.00105 AC: 47 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51302

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0000855 AC: 95 AN: 1111682

Other (OTH) AF: 0.00134 AC: 81 AN: 60326

GnomAD4 genome AF: 0.00292 AC: 445 AN: 152400 Hom.: 0 Cov.: 35 AF XY: 0.00276 AC XY: 206 AN XY: 74528

African (AFR) AF: 0.00988 AC: 411 AN: 41602

American (AMR) AF: 0.00131 AC: 20 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68048

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.00307

ESP6500AA AF: 0.00567 AC: 24

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000924 AC: 111

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4: BP4

May 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not specified Benign:2 Other:1

Jun 01, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 11, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Rothmund-Thomson syndrome type 2 Uncertain:1

Dec 22, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Hereditary cancer-predisposing syndrome Benign:1

Oct 09, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Baller-Gerold syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4-related disorder Benign:1

Mar 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.3
DANN	Benign	0.74
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0038	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.094
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.48	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.71
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.21
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs35101495; hg19: chr8-145737350;