rs766312203

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_004260.4(RECQL4):c.2412_2420delGGCCGGGCG(p.Ala805_Arg807del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000559 in 1,590,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R804R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.54

Publications

3 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 10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004260.4.

PP5

Variant 8-144513260-ACGCCCGGCC-A is Pathogenic according to our data. Variant chr8-144513260-ACGCCCGGCC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 239724.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.2412_2420delGGCCGGGCG	p.Ala805_Arg807del	disruptive_inframe_deletion	Exon 14 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RECQL4	ENST00000617875.6 link	c.2412_2420delGGCCGGGCG	p.Ala805_Arg807del	disruptive_inframe_deletion	Exon 14 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4 link	c.1341_1349delGGCCGGGCG	p.Ala448_Arg450del	disruptive_inframe_deletion	Exon 13 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6 link	c.634-131_634-123delGGCCGGGCG		intron_variant	Intron 5 of 7	5		ENSP00000477457.1
ENSG00000265393	ENST00000580385.1 link	n.272-343_272-335delCCCGGCCCG		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

151322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000635

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.0000412

AC:

AN:

218562

AF XY:

0.0000328

show subpopulations

Gnomad AFR exome

AF:

0.000543

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000403

AC:

AN:

1439460

Hom.:

AF XY:

0.0000335

AC XY:

AN XY:

715362

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33310

American (AMR)

AF:

0.0000452

AC:

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39384

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106970

Other (OTH)

AF:

0.000167

AC:

AN:

59798

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

AF:

0.000205

AC:

AN:

151436

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

73998

show subpopulations

African (AFR)

AF:

0.000634

AC:

AN:

41032

American (AMR)

AF:

0.000262

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67928

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

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:

0.000253

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 22, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in unrelated patients with RECQL4-related phenotype referred for genetic testing at GeneDx and in published literature (Colombo et al., 2018); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29642415, 31604778) -

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

Pathogenic:1

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rothmund-Thomson syndrome type 2

Pathogenic:1

Oct 26, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 supporting, PM2 moderate, PM3 moderate, PM4 moderate -

Baller-Gerold syndrome

Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2412_2420del, results in the deletion of 3 amino acid(s) of the RECQL4 protein (p.Ala805_Arg807del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766312203, gnomAD 0.06%). This variant has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 29642415, 31604778; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 239724). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.5

Mutation Taster

=31/169

disease causing (ClinVar)

(source)

Splicing

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