rs754735053

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_004260.4(RECQL4):​c.1568G>C​(p.Ser523Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,611,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

1
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 8-144514988-C-G is Benign according to our data. Variant chr8-144514988-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.1568G>C p.Ser523Thr missense_variant 9/21 ENST00000617875.6 NP_004251.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.1568G>C p.Ser523Thr missense_variant 9/211 NM_004260.4 ENSP00000482313 P1
RECQL4ENST00000621189.4 linkuse as main transcriptc.497G>C p.Ser166Thr missense_variant 8/201 ENSP00000483145
RECQL4ENST00000532846.2 linkuse as main transcriptc.425G>C p.Ser142Thr missense_variant 5/95 ENSP00000476551
RECQL4ENST00000688394.1 linkuse as main transcriptn.591G>C non_coding_transcript_exon_variant 3/4

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152186
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000246
AC:
60
AN:
244018
Hom.:
0
AF XY:
0.000240
AC XY:
32
AN XY:
133330
show subpopulations
Gnomad AFR exome
AF:
0.0000675
Gnomad AMR exome
AF:
0.000117
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000132
Gnomad FIN exome
AF:
0.0000476
Gnomad NFE exome
AF:
0.000427
Gnomad OTH exome
AF:
0.000505
GnomAD4 exome
AF:
0.000410
AC:
599
AN:
1459330
Hom.:
0
Cov.:
33
AF XY:
0.000405
AC XY:
294
AN XY:
725822
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000202
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.0000385
Gnomad4 NFE exome
AF:
0.000496
Gnomad4 OTH exome
AF:
0.000332
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152304
Hom.:
0
Cov.:
34
AF XY:
0.000336
AC XY:
25
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000426
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000225
Hom.:
0
Bravo
AF:
0.000506
ExAC
AF:
0.000232
AC:
28
EpiCase
AF:
0.000436
EpiControl
AF:
0.000655

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2021The c.1568G>C (p.S523T) alteration is located in exon 9 (coding exon 9) of the RECQL4 gene. This alteration results from a G to C substitution at nucleotide position 1568, causing the serine (S) at amino acid position 523 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Rothmund-Thomson syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalAug 19, 2020- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jul 30, 2021- -
Baller-Gerold syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 523 of the RECQL4 protein (p.Ser523Thr). This variant is present in population databases (rs754735053, gnomAD 0.05%). This missense change has been observed in cis with c.1573del (p.Cys525Alafs*33) in individual(s) with RAPADILINO, Baller-Gerold syndrome, and Rothmund–Thomson syndrome (PMID: 12838562, 15964893, 27247962, 29367366, 29642415). This variant has not been reported in isolation in the literature in individuals affected with RECQL4-related conditions. This variant is also known as g.2881G>C. ClinVar contains an entry for this variant (Variation ID: 259258). 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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022RECQL4: BP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
23
DANN
Benign
0.75
DEOGEN2
Benign
0.032
T;T
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.0069
T
MetaRNN
Uncertain
0.47
T;T
PrimateAI
Benign
0.39
T
Sift4G
Benign
0.096
T;D
Polyphen
0.64
.;P
Vest4
0.81
MVP
0.79
GERP RS
4.6
Varity_R
0.22
gMVP
0.56

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

LitVar

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

Other links and lift over

dbSNP: rs754735053; hg19: chr8-145740372; COSMIC: COSV104618514; COSMIC: COSV104618514; API