8-144514991-C-T

Position:

chr8-144514991-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_004260.4(RECQL4):c.1565G>A(p.Arg522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,611,498 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.019 ( 90 hom., cov: 34)

Exomes 𝑓: 0.0030 ( 112 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 2.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_004260.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0043632984).

BP6

Variant 8-144514991-C-T is Benign according to our data. Variant chr8-144514991-C-T is described in ClinVar as [Benign]. Clinvar id is 135176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514991-C-T is described in Lovd as [Benign]. Variant chr8-144514991-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.1565G>A	p.Arg522His	missense_variant	9/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.1565G>A	p.Arg522His	missense_variant	9/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.494G>A	p.Arg165His	missense_variant	8/20	1
RECQL4	ENST00000532846.2 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	5/9	5
RECQL4	ENST00000688394.1 linkuse as main transcript	n.588G>A		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2942

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0639

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00650

AC:

1586

AN:

243834

Hom.:

AF XY:

0.00542

AC XY:

722

AN XY:

133236

show subpopulations

Gnomad AFR exome

AF:

0.0654

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000627

Gnomad FIN exome

AF:

0.000334

Gnomad NFE exome

AF:

0.000737

Gnomad OTH exome

AF:

0.00454

GnomAD4 exome

AF:

0.00298

AC:

4348

AN:

1459290

Hom.:

112

Cov.:

AF XY:

0.00274

AC XY:

1986

AN XY:

725830

show subpopulations

Gnomad4 AFR exome

AF:

0.0696

Gnomad4 AMR exome

AF:

0.00455

Gnomad4 ASJ exome

AF:

0.0365

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000592

Gnomad4 FIN exome

AF:

0.000289

Gnomad4 NFE exome

AF:

0.000350

Gnomad4 OTH exome

AF:

0.00629

GnomAD4 genome

AF:

0.0194

AC:

2955

AN:

152208

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1413

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0640

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.0392

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.0219

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0674

AC:

289

ESP6500EA

AF:

0.00247

AC:

ExAC

AF:

0.00696

AC:

839

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.000774

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	This variant is associated with the following publications: (PMID: 30651579, 30306255) -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.060

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0044

T;T

PrimateAI

Benign

0.38

Sift4G

Benign

0.10

T;T

Polyphen

0.96

.;D

Vest4

0.47

MVP

0.75

GERP RS

5.5

Varity_R

0.18

gMVP

0.54

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