chr8-144513139-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004260.4(RECQL4):c.2464-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000795 in 1,558,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 splice_acceptor, intron

Scores

Splicing: ADA: 0.01681

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.88

Publications

8 publications found

Variant links:

COSMIC-nc: COSV52882660

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

RECQL4 links:

ENSG00000265393 (HGNC:):

ENSG00000265393 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.6, offset of -11, new splice context is: ccaccccaccctcatgaaAGttg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144513139-C-G is Pathogenic according to our data. Variant chr8-144513139-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 94889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.2464-1G>C		splice_acceptor_variant, intron_variant	Intron 14 of 20	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RECQL4	ENST00000617875.6 link	c.2464-1G>C	splice_acceptor_variant, intron_variant	Intron 14 of 20	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4 link	c.1393-1G>C	splice_acceptor_variant, intron_variant	Intron 13 of 19	1		ENSP00000483145.1
RECQL4	ENST00000534626.6 link	c.634-1G>C	splice_acceptor_variant, intron_variant	Intron 5 of 7	5		ENSP00000477457.1
ENSG00000265393	ENST00000580385.1 link	n.271+302C>G	intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.000120

AC:

AN:

149460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000975

GnomAD2 exomes

AF:

0.000105

AC:

AN:

200494

AF XY:

0.0000922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00310

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

106

AN:

1409346

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

694262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32618

American (AMR)

AF:

0.00

AC:

AN:

41370

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

23074

East Asian (EAS)

AF:

0.00

AC:

AN:

38896

South Asian (SAS)

AF:

0.00

AC:

AN:

78334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.0000249

AC:

AN:

1084390

Other (OTH)

AF:

0.000189

AC:

AN:

58164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000120

AC:

AN:

149460

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39886

American (AMR)

AF:

0.00

AC:

AN:

14836

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67840

Other (OTH)

AF:

0.000975

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000420

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 03, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 32775946, 18716613, 30687805, 34869606, 35833951, 31794323, 33077847, 37331604, 38413718, 29625052, 36451132, 12734318, 31887429, 36744932) -

Mar 04, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RECQL4: PVS1 -

Rothmund-Thomson syndrome type 2

Pathogenic:2

Aug 01, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RECQL4 c.2464-1G>C intronic change results in a G to C substitution at the -1 position of intron 14 of the RECQL4 gene and is predicted to disrupt the acceptor splice site. This variant has been identified in the homozygous state in siblings with clinical features of Rothmund-Thomson syndrome (PMID: 12734318), and in the compound heterozygous state in an unrelated individual with clinical features of Rothmund-Thomson syndrome (PMID: 18716613). It has also been identified as heterozygous in at least one individual with leiomyosarcoma (PMID: 29625052). This variant has a maximum founder subpopulation frequency of 0.31% and a maximum non-founder subpopulation frequency of 0.0011% in gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic. -

Feb 09, 2023

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The homozygous c.2464-1G>C variant identified in the RECQL4 gene is a canonical splice variant within intron 14/20, and is predicted to lead to aberrant splicing by in silico algorithm SpliceAI (delta score: 0.98 for an acceptor loss -1bp). This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.2.1, BRAVO-TOPMed, All of Us) with highest allele frequency in BRAVO-TOPMed (29 heterozygotes, 0 homozygotes, allele frequency: 1.10e-4), suggesting it is not a common benign variant in the populations represented in those databases. The c.2464-1G>C variant in RECQL4 is reported in ClinVar as Pathogenic (VarID:94889; 2 stars, 3 submissions, no conflicts), and has been previously reported in homozygous state in two siblings with a clinical diagnosis of Rothmund-Thomson syndrome [PMID:12734318] and in compound heterozygosity with a different canonical splice variant in an unrelated patient with a clinical diagnosis of Rothmund-Thomson syndrome [PMID:18716613]. Given its expected deleterious nature, low frequency in population databases, and presence in several affected individuals in the literature in both homozygous state and in compound heterozygosity, the homozygous c.2464-1G>C variant identified in the RECQL4 gene is reported as Pathogenic. -

Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2

Pathogenic:1

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baller-Gerold syndrome

Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 14 of the RECQL4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). This variant is present in population databases (rs398124117, gnomAD 0.3%). Disruption of this splice site has been observed in individual(s) with clinical features of Rothmund-Thomson syndrome (PMID: 12734318, 18716613, 29625052). It has also been observed to segregate with disease in related individuals. This variant is also known as g.4615G>C. ClinVar contains an entry for this variant (Variation ID: 94889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.9

GERP RS

4.9

PromoterAI

-0.0076

Neutral

(source)

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.017

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over