8-144513139-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004260.4(RECQL4):c.2464-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000142 in 1,409,346 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 splice_acceptor, intron

Scores

Splicing: ADA: 0.02584

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.88

Publications

8 publications found

Variant links:

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 12 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-T is Pathogenic according to our data. Variant chr8-144513139-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 577322.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RECQL4	NM_004260.4	MANE Select	c.2464-1G>A	splice_acceptor intron	N/A	NP_004251.4
RECQL4	NM_001413019.1		c.2464-1G>A	splice_acceptor intron	N/A	NP_001399948.1
RECQL4	NM_001413036.1		c.2464-1G>A	splice_acceptor intron	N/A	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2464-1G>A	splice_acceptor intron	N/A	ENSP00000482313.2
RECQL4	ENST00000621189.4	TSL:1	c.1393-1G>A	splice_acceptor intron	N/A	ENSP00000483145.1
RECQL4	ENST00000534626.6	TSL:5	c.634-1G>A	splice_acceptor intron	N/A	ENSP00000477457.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000499

AC:

AN:

200494

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1409346

Hom.:

Cov.:

AF XY:

0.00

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:

0.00

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:

0.00000184

AC:

AN:

1084390

Other (OTH)

AF:

0.00

AC:

AN:

58164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000841

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Baller-Gerold syndrome

Pathogenic:1

Mar 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Donor and acceptor splice site variants 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). A different variant affecting this nucleotide (c.2464-1G>C) has been determined to be pathogenic (PMID:¬†12734318,¬†18716613). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. This variant has not been reported in the literature in individuals affected with RECQL4-related disease. This variant is present in population databases (rs398124117, ExAC 0.003%). This sequence change affects a donor splice site in intron 14 of the RECQL4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.9

GERP RS

4.9

PromoterAI

-0.0022

Neutral

(source)

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.026

dbscSNV1_RF

Benign

0.044

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.39

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over