8-144513286-C-T

Position:

chr8-144513286-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004260.4(RECQL4):c.2395G>A(p.Val799Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,598,680 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 33)

Exomes 𝑓: 0.027 ( 675 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.27

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010660559).

BP6

Variant 8-144513286-C-T is Benign according to our data. Variant chr8-144513286-C-T is described in ClinVar as [Benign]. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in Lovd as [Benign]. Variant chr8-144513286-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2613/152246) while in subpopulation NFE AF= 0.0282 (1919/67988). AF 95% confidence interval is 0.0272. There are 29 homozygotes in gnomad4. There are 1211 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2395G>A	p.Val799Met	missense_variant	14/21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2395G>A	p.Val799Met	missense_variant	14/21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1324G>A	p.Val442Met	missense_variant	13/20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 linkuse as main transcript	c.633+130G>A		intron_variant		5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 linkuse as main transcript	n.272-320C>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2612

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0242

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0162

AC:

3646

AN:

225518

Hom.:

AF XY:

0.0160

AC XY:

2004

AN XY:

125386

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0000571

Gnomad SAS exome

AF:

0.00348

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0268

AC:

38695

AN:

1446434

Hom.:

675

Cov.:

AF XY:

0.0257

AC XY:

18493

AN XY:

719970

show subpopulations

Gnomad4 AFR exome

AF:

0.00452

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.00196

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00392

Gnomad4 FIN exome

AF:

0.0230

Gnomad4 NFE exome

AF:

0.0318

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0172

AC:

2613

AN:

152246

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1211

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0242

Gnomad4 NFE

AF:

0.0282

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0210

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.00537

AC:

ESP6500EA

AF:

0.0226

AC:

186

ExAC

AF:

0.0158

AC:

1883

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2020	Published in association with Rothmund-Thomson syndrome (Wang et al., 2003; Suter et al., 2016). Wang et al. reported that the V799M variant was observed in cis with the P1170L variant in their patient, making V799M's contribution to disease uncertain. Limited information on the patient was available from Suter et al. publication.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27247962, 12734318) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RECQL4: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Rothmund-Thomson syndrome type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Baller-Gerold syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.11

T;D

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.011

T;T

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Uncertain

0.59

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

.;D

Vest4

0.75

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.56

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