Variant chr8-144516313-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004260.4(RECQL4):c.806G>A(p.Trp269Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -2.87

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144516313-C-T is Pathogenic according to our data. Variant chr8-144516313-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6072.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144516313-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.806G>A	p.Trp269Ter	stop_gained	5/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.806G>A	p.Trp269Ter	stop_gained	5/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.-266G>A		5_prime_UTR_variant	4/20	1		ENSP00000483145
RECQL4	ENST00000524998.1 linkuse as main transcript	c.329G>A	p.Trp110Ter	stop_gained	3/4	3		ENSP00000476579
RECQL4	ENST00000534538.1 linkuse as main transcript	c.*610G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	3		ENSP00000476318

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242414

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132292

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457622

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000393

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Rapadilino syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

Baller-Gerold syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in an individual affected with RAPADILINO syndrome who was also reported to carry another pathogenic RECQL4 variant in trans (PMID: 12952869). ClinVar contains an entry for this variant (Variation ID: 6072). This variant is present in population databases (rs137853231, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Trp269*) in the RECQL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RECQL4 are known to be pathogenic (PMID: 12734318, 12952869). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0013

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Benign

0.59

FATHMM_MKL

Benign

0.014

Vest4

0.56

GERP RS

-3.5

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over