8-144513330-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):c.2351G>A(p.Arg784Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000904 in 1,603,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R784G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.80

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2351G>A	p.Arg784Gln	missense_variant	14/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2351G>A	p.Arg784Gln	missense_variant	14/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1280G>A	p.Arg427Gln	missense_variant	13/20	1
	ENST00000580385.1 linkuse as main transcript	n.272-276C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.634+86G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000987

AC:

AN:

233136

Hom.:

AF XY:

0.0000776

AC XY:

AN XY:

128946

show subpopulations

Gnomad AFR exome

AF:

0.0000699

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000205

Gnomad EAS exome

AF:

0.0000565

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000345

Gnomad NFE exome

AF:

0.0000658

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000793

AC:

115

AN:

1451090

Hom.:

Cov.:

AF XY:

0.0000831

AC XY:

AN XY:

722332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000253

Gnomad4 NFE exome

AF:

0.0000711

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000197

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000753

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Baller-Gerold syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 784 of the RECQL4 protein (p.Arg784Gln). This variant is present in population databases (rs536096413, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 459395). 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 not expected to disrupt RECQL4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2021

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Pathogenic

0.22

Cadd

Pathogenic

Dann

Benign

0.91

DEOGEN2

Benign

0.25

T;D

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.67

D;D

PrimateAI

Uncertain

0.56

Sift4G

Uncertain

0.051

T;T

Polyphen

1.0

.;D

Vest4

0.65

MVP

0.72

GERP RS

5.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.2

Varity_R

0.52

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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