rs756627

Positions:

• chr8-144511903-G-A
• chr8-144511903-G-C

Variant summary

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

The NM_001413036.1(RECQL4):​c.3401C>T​(p.Ala1134Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,609,516 control chromosomes in the GnomAD database, including 175,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13393 hom., cov: 35)
  • Exomes 𝑓: 0.47 (162198 hom.)
• Consequence: RECQL4 NM_001413036.1 missense, splice_region
• Scores: Splicing: ADA: 0.00003801
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.00

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8563938E-5).
• BP6: Variant 8-144511903-G-A is Benign according to our data. Variant chr8-144511903-G-A is described in ClinVar as [Benign]. Clinvar id is 94894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144511903-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.3393+8C>T		splice_region_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.3393+8C>T		splice_region_variant, intron_variant		1	NM_004260.4	ENSP00000482313.2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58955 AN: 152096 Hom.: 13389 Cov.: 35

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.476 AC: 116530 AN: 244932 Hom.: 28974 AF XY: 0.482 AC XY: 64384 AN XY: 133688

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.493

Gnomad SAS exome AF: 0.567

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.467 AC: 680494 AN: 1457302 Hom.: 162198 Cov.: 49 AF XY: 0.471 AC XY: 341695 AN XY: 724980

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.565

Gnomad4 FIN exome AF: 0.494

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.387 AC: 58965 AN: 152214 Hom.: 13393 Cov.: 35 AF XY: 0.395 AC XY: 29397 AN XY: 74408

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.493

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.471

Gnomad4 OTH AF: 0.418

Alfa AF: 0.443 Hom.: 21286

Bravo AF: 0.375

TwinsUK AF: 0.457 AC: 1696

ALSPAC AF: 0.469 AC: 1806

ESP6500AA AF: 0.139 AC: 598

ESP6500EA AF: 0.457 AC: 3883

ExAC AF: 0.463 AC: 55704

Asia WGS AF: 0.529 AC: 1838 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.471

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.60
DEOGEN2	Benign	0.0024	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.000029	T
Sift4G	Benign	0.30	T
GERP RS		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.10		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: rs756627; hg19: chr8-145737286; COSMIC: COSV56739629; COSMIC: COSV56739629;