12-21470228-G-A

Variant names:

• chr12-21470228-G-A
• NM_002907.4:c.1916C>T

Variant summary

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

The NM_002907.4(RECQL):​c.1916C>T​(p.Thr639Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RECQL NM_002907.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.602

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=0.110078216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1916C>T	p.Thr639Ile	missense_variant	Exon 15 of 15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1474G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL	ENST00000444129.7	c.1916C>T	p.Thr639Ile	missense_variant	Exon 15 of 15	2	NM_002907.4	ENSP00000416739.2
RECQL	ENST00000421138.6	c.1916C>T	p.Thr639Ile	missense_variant	Exon 16 of 16	1		ENSP00000395449.2
PYROXD1	ENST00000240651.14	c.*1474G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_024854.5	ENSP00000240651.9
PYROXD1	ENST00000538582.5	c.*1474G>A		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000438505.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458056 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 725140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	.;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.063
Sift	Benign	0.10	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0080	B;B
Vest4		0.16
MutPred		0.21		Loss of phosphorylation at T639 (P = 0.015);Loss of phosphorylation at T639 (P = 0.015);
MVP		0.66
MPC		1.8
ClinPred		0.39	T
GERP RS		4.2
Varity_R		0.039
gMVP		0.041

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21623162;