chr12-21470200-A-T

Position:

• chr12-21470200-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000240651.14(PYROXD1):​c.*1446A>T variant causes a 3 prime UTR 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: PYROXD1 ENST00000240651.14 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.603

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]

ACMG classification

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=0.11620033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1944T>A	p.Asp648Glu	missense_variant	15/15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1446A>T		3_prime_UTR_variant	12/12	ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL	ENST00000444129.7	c.1944T>A	p.Asp648Glu	missense_variant	15/15	2	NM_002907.4	ENSP00000416739	P1
RECQL	ENST00000421138.6	c.1944T>A	p.Asp648Glu	missense_variant	16/16	1		ENSP00000395449	P1
PYROXD1	ENST00000240651.14	c.*1446A>T		3_prime_UTR_variant	12/12	1	NM_024854.5	ENSP00000240651	P1
PYROXD1	ENST00000538582.5	c.*1446A>T		3_prime_UTR_variant	12/12	2		ENSP00000438505

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2024

The p.D648E variant (also known as c.1944T>A), located in coding exon 14 of the RECQL gene, results from a T to A substitution at nucleotide position 1944. The aspartic acid at codon 648 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	D;D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.040
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.044	B;B
Vest4		0.19
MutPred		0.14		Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);
MVP		0.59
MPC		1.9
ClinPred		0.22	T
GERP RS		2.7
Varity_R		0.047
gMVP		0.018

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21623134;