8-144513443-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004260.4(RECQL4):c.2238G>A(p.Ala746=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,609,742 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A746A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (28 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.18

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144513443-C-T is Benign according to our data. Variant chr8-144513443-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513443-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00939 (1431/152350) while in subpopulation AFR AF= 0.027 (1124/41568). AF 95% confidence interval is 0.0257. There are 10 homozygotes in gnomad4. There are 684 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.2238G>A	p.Ala746=	synonymous_variant	14/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2238G>A	p.Ala746=	synonymous_variant	14/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1167G>A	p.Ala389=	synonymous_variant	13/20	1
	ENST00000580385.1	n.272-163C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.609G>A	p.Ala203=	synonymous_variant	5/8	5

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1416 AN: 152232 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00342 AC: 830 AN: 242480 Hom.: 5 AF XY: 0.00309 AC XY: 411 AN XY: 132956

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00293

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00453

GnomAD4 exome AF: 0.00310 AC: 4515 AN: 1457392 Hom.: 28 Cov.: 47 AF XY: 0.00295 AC XY: 2142 AN XY: 725182

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00471

GnomAD4 genome AF: 0.00939 AC: 1431 AN: 152350 Hom.: 10 Cov.: 33 AF XY: 0.00918 AC XY: 684 AN XY: 74504

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00506 Hom.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2021

- -

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

Jan 31, 2024

- -

RECQL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.21
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs35215952; hg19: chr8-145738827; COSMIC: COSV104618491; COSMIC: COSV104618491;