chr8-144515323-CA-C

Variant names:

• chr8-144515323-CA-C
• rs386833843
• NM_004260.4:c.1390+2delT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004260.4(RECQL4):​c.1390+2delT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,612,378 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: RECQL4 NM_004260.4 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.01
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.036393713 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-144515323-CA-C is Pathogenic according to our data. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144515323-CA-C is described in CliVar as Pathogenic. Clinvar id is 56398.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1390+2delT		splice_donor_variant, intron_variant	Intron 7 of 20	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1390+2delT		splice_donor_variant, intron_variant	Intron 7 of 20	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.319+2delT		splice_donor_variant, intron_variant	Intron 6 of 19	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.274+2delT		splice_donor_variant, intron_variant	Intron 3 of 8	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.413+2delT		splice_donor_variant, intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152250 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000389 AC: 96 AN: 246886 AF XY: 0.000424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000145 AC: 211 AN: 1460010 Hom.: 1 Cov.: 33 AF XY: 0.000138 AC XY: 100 AN XY: 726222

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00374 AC: 195 AN: 52170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111594

Other (OTH) AF: 0.0000829 AC: 5 AN: 60340

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152368 Hom.: 0 Cov.: 34 AF XY: 0.000617 AC XY: 46 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Rapadilino syndrome Pathogenic:2

Nov 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Baller-Gerold syndrome Pathogenic:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 7 of the RECQL4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs386833843, gnomAD 0.4%). Disruption of this splice site has been observed in individual(s) with RAPADILINO syndrome (PMID: 12952869, 18716613). It is commonly reported in individuals of Finnish ancestry (PMID: 12952869, 18716613). This variant is also known as IVS7+2delT. ClinVar contains an entry for this variant (Variation ID: 56398). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects RECQL4 function (PMID: 17250975, 22885111). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 12952869, 22885111). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386833843; hg19: chr8-145740707;