12-21468957-T-C

Position:

• chr12-21468957-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002907.4(RECQL):​c.*1237A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 494,508 control chromosomes in the GnomAD database, including 39,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9179 hom., cov: 32)
  • Exomes 𝑓: 0.41 (30137 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0160

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-21468957-T-C is Benign according to our data. Variant chr12-21468957-T-C is described in ClinVar as [Benign]. Clinvar id is 1275426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL	NM_002907.4	c.*1237A>G		3_prime_UTR_variant	15/15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*203T>C		3_prime_UTR_variant	12/12	ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14	c.*203T>C		3_prime_UTR_variant	12/12	1	NM_024854.5	ENSP00000240651	P1
RECQL	ENST00000444129.7	c.*1237A>G		3_prime_UTR_variant	15/15	2	NM_002907.4	ENSP00000416739	P1
PYROXD1	ENST00000538582.5	c.*203T>C		3_prime_UTR_variant	12/12	2		ENSP00000438505
PYROXD1	ENST00000375266.8			downstream_gene_variant		5		ENSP00000364415

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47339 AN: 151884 Hom.: 9182 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.284

GnomAD4 exome AF: 0.412 AC: 141145 AN: 342506 Hom.: 30137 Cov.: 5 AF XY: 0.418 AC XY: 74986 AN XY: 179542

Gnomad4 AFR exome AF: 0.0695

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.378

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.373

GnomAD4 genome AF: 0.311 AC: 47333 AN: 152002 Hom.: 9179 Cov.: 32 AF XY: 0.319 AC XY: 23665 AN XY: 74264

Gnomad4 AFR AF: 0.0733

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.280

Alfa AF: 0.361 Hom.: 2569

Bravo AF: 0.283

Asia WGS AF: 0.355 AC: 1223 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.72

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

Other links and lift over

dbSNP: rs7319; hg19: chr12-21621891;