8-144513713-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.2059-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000327 in 1,529,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 splice_acceptor, intron

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 5.85

Publications

5 publications found

Variant links:

COSMIC-nc: COSV52883043

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, SUPPORTIVE Submitted by: Orphanet, G2P
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144513713-C-T is Pathogenic according to our data. Variant chr8-144513713-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56404.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	UniProt
RECQL4	NM_004260.4	MANE Select	c.2059-1G>A	splice_acceptor intron	N/A	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.2059-1G>A	splice_acceptor intron	N/A	NP_001399948.1
RECQL4	NM_001413036.1		c.2059-1G>A	splice_acceptor intron	N/A	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2059-1G>A	splice_acceptor intron	N/A	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.988-1G>A	splice_acceptor intron	N/A	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.1966-1G>A	splice_acceptor intron	N/A	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.00000699

AC:

AN:

143088

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1386064

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

683478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30694

American (AMR)

AF:

0.00

AC:

AN:

35210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24578

East Asian (EAS)

AF:

0.00

AC:

AN:

35018

South Asian (SAS)

AF:

0.00

AC:

AN:

79056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00000373

AC:

AN:

1071718

Other (OTH)

AF:

0.00

AC:

AN:

57030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.00000699

AC:

AN:

143088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69558

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37626

American (AMR)

AF:

0.00

AC:

AN:

14222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00

AC:

AN:

4950

South Asian (SAS)

AF:

0.00

AC:

AN:

4350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65632

Other (OTH)

AF:

0.00

AC:

AN:

1938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Baller-Gerold syndrome (2)

Rapadilino syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Uncertain

0.97

PhyloP100

5.8

GERP RS

5.0

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.66

Position offset: -2

DS_AL_spliceai

0.91

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

Computational scores

Splicing

Publications

Other links and lift over