rs35346077

chr8-144511740-G-Achr8-144511740-G-Cchr8-144511740-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004260.4(RECQL4):c.3443C>T(p.Ser1148Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,612,600 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1148C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0111530125).
• BP6: Variant 8-144511740-G-A is Benign according to our data. Variant chr8-144511740-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135153.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=2, Uncertain_significance=1, Likely_benign=3}. Variant chr8-144511740-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.3443C>T	p.Ser1148Phe	missense_variant	20/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.3443C>T	p.Ser1148Phe	missense_variant	20/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00141 AC: 350 AN: 247740 Hom.: 1 AF XY: 0.00148 AC XY: 200 AN XY: 134974

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00239

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00210 AC: 3070 AN: 1460222 Hom.: 3 Cov.: 36 AF XY: 0.00207 AC XY: 1501 AN XY: 726388

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.000135

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152378 Hom.: 0 Cov.: 34 AF XY: 0.00101 AC XY: 75 AN XY: 74514

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.00153 AC: 13

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	RECQL4: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2016	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 04, 2021

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Benign	0.84
DEOGEN2	Benign	0.047	T;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.011	T;T;T
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.19	T;T;D
Polyphen		0.99	.;D;.
Vest4		0.49
MVP		0.72
GERP RS		5.0
Varity_R		0.068
gMVP		0.33

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: rs35346077; hg19: chr8-145737123; COSMIC: COSV56743533; COSMIC: COSV56743533;