chr8-144514092-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_004260.4(RECQL4):c.1894A>G(p.Met632Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,449,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M632I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.80

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 35 uncertain in NM_004260.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07291889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.1894A>G	p.Met632Val	missense_variant	Exon 12 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 link	c.1894A>G	p.Met632Val	missense_variant	Exon 12 of 21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 link	c.823A>G	p.Met275Val	missense_variant	Exon 11 of 20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 link	c.262A>G	p.Met88Val	missense_variant	Exon 3 of 8	5		ENSP00000477457.1	V9GZ64
RECQL4	ENST00000532846.2 link	c.748A>G	p.Met250Val	missense_variant	Exon 8 of 9	5		ENSP00000476551.1	V9GYA3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

220932

AF XY:

0.0000247

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1449562

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

720348

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

43188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25788

East Asian (EAS)

AF:

0.00

AC:

AN:

39088

South Asian (SAS)

AF:

0.000165

AC:

AN:

84624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1107244

Other (OTH)

AF:

0.00

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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.:

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Baller-Gerold syndrome

Uncertain:1

Nov 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 632 of the RECQL4 protein (p.Met632Val). This variant is present in population databases (rs745309255, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 459353). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RECQL4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.11

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.029

T;T

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.073

T;T

PhyloP100

-1.8

PrimateAI

Benign

0.29

Sift4G

Benign

0.17

T;T

Polyphen

0.0090

.;B

Vest4

0.35

MVP

0.40

GERP RS

-11

PromoterAI

-0.00020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.46

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over