rs4244611

Positions:

• chr8-144514540-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):​c.1621-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,607,346 control chromosomes in the GnomAD database, including 175,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13353 hom., cov: 34)
  • Exomes 𝑓: 0.47 (162403 hom.)
• Consequence: RECQL4 NM_004260.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.100

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-144514540-G-A is Benign according to our data. Variant chr8-144514540-G-A is described in ClinVar as [Benign]. Clinvar id is 94886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514540-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1621-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1621-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004260.4	ENSP00000482313	P1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58849 AN: 152050 Hom.: 13348 Cov.: 34

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.422

GnomAD3 exomes AF: 0.477 AC: 114486 AN: 240224 Hom.: 28304 AF XY: 0.482 AC XY: 63204 AN XY: 131158

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.469

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.468 AC: 680427 AN: 1455178 Hom.: 162403 Cov.: 39 AF XY: 0.472 AC XY: 341259 AN XY: 723420

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.564

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.452

GnomAD4 genome AF: 0.387 AC: 58860 AN: 152168 Hom.: 13353 Cov.: 34 AF XY: 0.395 AC XY: 29362 AN XY: 74400

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.580

Gnomad4 FIN AF: 0.502

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.421

Alfa AF: 0.402 Hom.: 3201

Bravo AF: 0.374

Asia WGS AF: 0.533 AC: 1852 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Rothmund-Thomson syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Baller-Gerold syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Rapadilino syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.55
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs4244611; hg19: chr8-145739924; COSMIC: COSV52878087; COSMIC: COSV52878087;