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GeneBe

12-21470228-G-T

Variant summary

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

The NM_002907.4(RECQL):c.1916C>A(p.Thr639Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Consequence

RECQL
NM_002907.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.602
Variant links:
Genes affected
RECQL (HGNC:9948): (RecQ like helicase) The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. The encoded protein is involved in the processing of Holliday junctions, the suppression of sister chromatid exchanges, telomere maintenance, and is required for genotoxic stress resistance. Defects in this gene have been associated with several types of cancer. [provided by RefSeq, Jan 2017]
PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

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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=0.121346146).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RECQLNM_002907.4 linkuse as main transcriptc.1916C>A p.Thr639Lys missense_variant 15/15 ENST00000444129.7
PYROXD1NM_024854.5 linkuse as main transcriptc.*1474G>T 3_prime_UTR_variant 12/12 ENST00000240651.14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RECQLENST00000444129.7 linkuse as main transcriptc.1916C>A p.Thr639Lys missense_variant 15/152 NM_002907.4 P1
RECQLENST00000421138.6 linkuse as main transcriptc.1916C>A p.Thr639Lys missense_variant 16/161 P1
PYROXD1ENST00000240651.14 linkuse as main transcriptc.*1474G>T 3_prime_UTR_variant 12/121 NM_024854.5 P1Q8WU10-1
PYROXD1ENST00000538582.5 linkuse as main transcriptc.*1474G>T 3_prime_UTR_variant 12/122 Q8WU10-2

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248044
Hom.:
0
AF XY:
0.00000746
AC XY:
1
AN XY:
134002
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
38
GnomAD4 genome
Cov.:
29
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 18, 2024This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 639 of the RECQL protein (p.Thr639Lys). This variant is present in population databases (rs750537649, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RECQL-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
0.083
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.32
Cadd
Benign
6.2
Dann
Benign
0.97
DEOGEN2
Benign
0.19
T;T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.88
D
M_CAP
Benign
0.0069
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.55
N;N
REVEL
Benign
0.084
Sift
Benign
0.061
T;T
Sift4G
Benign
0.49
T;T
Polyphen
0.037
B;B
Vest4
0.17
MutPred
0.34
Gain of catalytic residue at K637 (P = 0.0142);Gain of catalytic residue at K637 (P = 0.0142);
MVP
0.64
MPC
2.1
ClinPred
0.30
T
GERP RS
4.2
Varity_R
0.049
gMVP
0.048

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: rs750537649; hg19: chr12-21623162; API