chr8-144512318-C-T

Position:

chr8-144512318-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10O:1

Conservation

PhyloP100: -0.313

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]

RECQL4 links:

RECQL4 (HGNC:):

RECQL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, Uncertain_significance=3, not_provided=1, Benign=2}. 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/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.3062G>A	p.Arg1021Gln	missense_variant	18/21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.3062G>A	p.Arg1021Gln	missense_variant	18/21	1	NM_004260.4	ENSP00000482313.2		O94761

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

627

AN:

152264

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00401

AC XY:

540

AN XY:

134672

show subpopulations

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.:

Cov.:

AF XY:

0.00512

AC XY:

3716

AN XY:

726186

show subpopulations

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.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74518

show subpopulations

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.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00769

AC:

ExAC

AF:

0.00389

AC:

468

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00747

EpiControl

AF:

0.00717

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RECQL4: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	This variant is associated with the following publications: (PMID: 15897384, 30007837, 12734318, 24728327) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2015	- -

Rothmund-Thomson syndrome type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Oct 16, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2021

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. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 25, 2021

- -

Baller-Gerold syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

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

LIST_S2

Benign

0.23

T;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0053

T;T;T

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over