8-144514533-T-C

Position:

• chr8-144514533-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000617875.6(RECQL4):​c.1621-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,609,830 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00076 (8 hom.)
• Consequence: RECQL4 ENST00000617875.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.56

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=-0.85).
• BP6: Variant 8-144514533-T-C is Benign according to our data. Variant chr8-144514533-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 239701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514533-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000758 (1105/1457834) while in subpopulation MID AF= 0.00678 (39/5756). AF 95% confidence interval is 0.00592. There are 8 homozygotes in gnomad4_exome. There are 720 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1621-8A>G		splice_region_variant, 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.1621-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004260.4	ENSP00000482313	P1

Frequencies

GnomAD3 genomes AF: 0.000810 AC: 123 AN: 151878 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00135 AC: 329 AN: 243254 Hom.: 1 AF XY: 0.00172 AC XY: 228 AN XY: 132858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00628

Gnomad FIN exome AF: 0.0000948

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000758 AC: 1105 AN: 1457834 Hom.: 8 Cov.: 36 AF XY: 0.000993 AC XY: 720 AN XY: 725000

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.0000387

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000796 AC: 121 AN: 151996 Hom.: 3 Cov.: 34 AF XY: 0.00102 AC XY: 76 AN XY: 74302

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000733 Hom.: 0

Bravo AF: 0.000733

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RECQL4: BP4, BS2 -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2017	- -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 30, 2021

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.68

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: rs373357384; hg19: chr8-145739917;