rs375250269

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004260.4(RECQL4):​c.2486G>A​(p.Arg829His) variant causes a missense change. The variant allele was found at a frequency of 0.0000492 in 1,563,552 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

1
5
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.52
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16922417).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.2486G>A p.Arg829His missense_variant 15/21 ENST00000617875.6 NP_004251.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.2486G>A p.Arg829His missense_variant 15/211 NM_004260.4 ENSP00000482313 P1
RECQL4ENST00000621189.4 linkuse as main transcriptc.1415G>A p.Arg472His missense_variant 14/201 ENSP00000483145
ENST00000580385.1 linkuse as main transcriptn.271+279C>T intron_variant, non_coding_transcript_variant 3
RECQL4ENST00000534626.6 linkuse as main transcriptc.659G>A p.Arg220His missense_variant 6/85 ENSP00000477457

Frequencies

GnomAD3 genomes
AF:
0.0000268
AC:
4
AN:
149506
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000632
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000929
AC:
19
AN:
204446
Hom.:
0
AF XY:
0.000127
AC XY:
14
AN XY:
110474
show subpopulations
Gnomad AFR exome
AF:
0.0000763
Gnomad AMR exome
AF:
0.0000968
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000664
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000516
AC:
73
AN:
1413954
Hom.:
0
Cov.:
66
AF XY:
0.0000732
AC XY:
51
AN XY:
697000
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000724
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000103
Gnomad4 SAS exome
AF:
0.000430
Gnomad4 FIN exome
AF:
0.0000203
Gnomad4 NFE exome
AF:
0.0000286
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000267
AC:
4
AN:
149598
Hom.:
0
Cov.:
34
AF XY:
0.0000137
AC XY:
1
AN XY:
72908
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000632
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.000243
AC:
1
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.000101
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 07, 2022In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Baller-Gerold syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 829 of the RECQL4 protein (p.Arg829His). This variant is present in population databases (rs375250269, gnomAD 0.07%). 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: 529019). 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 expected to disrupt RECQL4 protein function with a positive 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
0.13
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Benign
0.82
DEOGEN2
Benign
0.11
T;T
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.17
T;T
MutationAssessor
Uncertain
2.6
.;M
PrimateAI
Uncertain
0.51
T
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.97
.;D
Vest4
0.57
MVP
0.62
GERP RS
3.2
Varity_R
0.14
gMVP
0.70

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.

Other links and lift over

dbSNP: rs375250269; hg19: chr8-145738499; API