rs538535710

chr8-144513215-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004260.4(RECQL4):c.2463+3T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,568,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: RECQL4 NM_004260.4 splice_donor_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -4.47

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.2463+3T>C		splice_donor_region_variant, intron_variant		ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2463+3T>C		splice_donor_region_variant, intron_variant		1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1392+3T>C		splice_donor_region_variant, intron_variant		1
	ENST00000580385.1	n.271+378A>G		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.635-77T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000466 AC: 7 AN: 150218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000118 AC: 24 AN: 203320 Hom.: 0 AF XY: 0.0000796 AC XY: 9 AN XY: 113044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00113

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000473 AC: 67 AN: 1417846 Hom.: 0 Cov.: 47 AF XY: 0.0000570 AC XY: 40 AN XY: 701156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000591

Gnomad4 SAS exome AF: 0.000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000265

Gnomad4 OTH exome AF: 0.0000510

GnomAD4 genome AF: 0.0000466 AC: 7 AN: 150332 Hom.: 1 Cov.: 33 AF XY: 0.0000680 AC XY: 5 AN XY: 73498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000783

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Aug 29, 2023

The RECQL4 c.2463+3T>C intronic change results in a T to C substitution at the +3 position of intron 15 of the RECQL4 gene. This variant is predicted to disrupt the consensus splice site however RNA studies have not been performed. This variant has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1. To our knowledge, this variant has not been reported in the literature in individuals with RECQL4-associated disorders. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

This sequence change falls in intron 14 of the RECQL4 gene. It does not directly change the encoded amino acid sequence of the RECQL4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs538535710, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 239729). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.021
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs538535710; hg19: chr8-145738598;