8-144517415-T-C

Position:

chr8-144517415-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004260.4(RECQL4):c.212A>G(p.Glu71Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,569,994 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E71A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 56 hom., cov: 35)

Exomes 𝑓: 0.013 ( 381 hom. )

Consequence

RECQL4
NM_004260.4 missense, splice_region

Scores

Splicing: ADA: 0.02223

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.233

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002013743).

BP6

Variant 8-144517415-T-C is Benign according to our data. Variant chr8-144517415-T-C is described in ClinVar as [Benign]. Clinvar id is 135158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144517415-T-C is described in Lovd as [Benign]. Variant chr8-144517415-T-C is described in Lovd as [Likely_benign]. Variant chr8-144517415-T-C is described in Lovd as [Likely_pathogenic].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0572 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.212A>G	p.Glu71Gly	missense_variant, splice_region_variant	3/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.212A>G	p.Glu71Gly	missense_variant, splice_region_variant	3/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2015

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0470

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.00850

Gnomad SAS

AF:

0.0538

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.00840

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0234

AC:

4156

AN:

177752

Hom.:

129

AF XY:

0.0241

AC XY:

2372

AN XY:

98418

show subpopulations

Gnomad AFR exome

AF:

0.00694

Gnomad AMR exome

AF:

0.0565

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.00616

Gnomad SAS exome

AF:

0.0577

Gnomad FIN exome

AF:

0.00451

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0126

AC:

17918

AN:

1417774

Hom.:

381

Cov.:

AF XY:

0.0139

AC XY:

9795

AN XY:

702204

show subpopulations

Gnomad4 AFR exome

AF:

0.00719

Gnomad4 AMR exome

AF:

0.0592

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.00412

Gnomad4 SAS exome

AF:

0.0583

Gnomad4 FIN exome

AF:

0.00446

Gnomad4 NFE exome

AF:

0.00799

Gnomad4 OTH exome

AF:

0.0150

GnomAD4 genome

AF:

0.0133

AC:

2018

AN:

152220

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1123

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00568

Gnomad4 AMR

AF:

0.0470

Gnomad4 ASJ

AF:

0.0205

Gnomad4 EAS

AF:

0.00852

Gnomad4 SAS

AF:

0.0540

Gnomad4 FIN

AF:

0.00594

Gnomad4 NFE

AF:

0.00840

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.00557

Hom.:

Bravo

AF:

0.0146

ESP6500AA

AF:

0.00316

AC:

ESP6500EA

AF:

0.00348

AC:

ExAC

AF:

0.0160

AC:

1808

Asia WGS

AF:

0.0320

AC:

112

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

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	Nov 29, 2018	This variant is associated with the following publications: (PMID: 30651579, 12734318) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 12, 2022

This variant has been reported in the literature in at least 2 individuals: 1 with Rothmund-Thomson syndrome and 1 with sagittal craniosynostosis (Wang 2003 PMID:12734318, Sewda 2019 PMID:30651579). However, this variant is present in the Genome Aggregation Database (Highest reported MAF 4.7% (719/15286) including 41 homozygotes (https://gnomad.broadinstitute.org/variant/8-144517415-T-C?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:135158). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, this variant is not expected to cause disease and is classified as benign. -

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

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.22

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0020

PrimateAI

Uncertain

0.55

Sift4G

Benign

0.16

Polyphen

0.61

Vest4

0.066

GERP RS

3.8

Varity_R

0.21

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.022

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.42

Position offset: -1

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