8-144514287-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004260.4(RECQL4):​c.1780G>A​(p.Ala594Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,611,268 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A594V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.591

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06780407).
BP6
Variant 8-144514287-C-T is Benign according to our data. Variant chr8-144514287-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 583123.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RECQL4NM_004260.4 linkc.1780G>A p.Ala594Thr missense_variant Exon 11 of 21 ENST00000617875.6 NP_004251.4 O94761

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RECQL4ENST00000617875.6 linkc.1780G>A p.Ala594Thr missense_variant Exon 11 of 21 1 NM_004260.4 ENSP00000482313.2 O94761

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000205
AC:
5
AN:
244264
AF XY:
0.0000150
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:
0.0000273
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000254
AC:
37
AN:
1459120
Hom.:
0
Cov.:
36
AF XY:
0.0000262
AC XY:
19
AN XY:
725818
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33466
American (AMR)
AF:
0.00
AC:
0
AN:
44642
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26094
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51532
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.0000288
AC:
32
AN:
1111444
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60272
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.472
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41412
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.642
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.0000415
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1
Nov 02, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 594 of the RECQL4 protein (p.Ala594Thr). This variant is present in population databases (rs376364416, gnomAD 0.007%). 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: 583123). 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. -

RECQL4-related disorder Uncertain:1
Mar 27, 2024
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The RECQL4 c.1780G>A variant is predicted to result in the amino acid substitution p.Ala594Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ovarian cancer Benign:1
Jan 01, 2022
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
0.0020
DANN
Benign
0.63
DEOGEN2
Benign
0.0075
T;T
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.15
T;T
M_CAP
Benign
0.00044
T
MetaRNN
Benign
0.068
T;T
PhyloP100
-0.59
PrimateAI
Benign
0.33
T
Sift4G
Benign
0.61
T;T
Polyphen
0.0040
.;B
Vest4
0.080
MVP
0.71
GERP RS
-1.7
PromoterAI
0.023
Neutral
Varity_R
0.045
gMVP
0.34
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs376364416; hg19: chr8-145739671; API