12-21470188-T-G

Position:

• chr12-21470188-T-G

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.*6A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 1,610,240 control chromosomes in the GnomAD database, including 155,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11199 hom., cov: 30)
  • Exomes 𝑓: 0.44 (144294 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.78

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=-0.88).
• BP6: Variant 12-21470188-T-G is Benign according to our data. Variant chr12-21470188-T-G is described in ClinVar as [Benign]. Clinvar id is 1242890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL	NM_002907.4	c.*6A>C		3_prime_UTR_variant	15/15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1434T>G		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.*1434T>G		3_prime_UTR_variant	12/12	1	NM_024854.5	ENSP00000240651	P1
RECQL	ENST00000444129.7	c.*6A>C		3_prime_UTR_variant	15/15	2	NM_002907.4	ENSP00000416739	P1
RECQL	ENST00000421138.6	c.*6A>C		3_prime_UTR_variant	16/16	1		ENSP00000395449	P1
PYROXD1	ENST00000538582.5	c.*1434T>G		3_prime_UTR_variant	12/12	2		ENSP00000438505

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54483 AN: 151360 Hom.: 11202 Cov.: 30

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.431 AC: 107141 AN: 248366 Hom.: 23917 AF XY: 0.436 AC XY: 58518 AN XY: 134290

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.424

Gnomad SAS exome AF: 0.493

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.435

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.440 AC: 642521 AN: 1458762 Hom.: 144294 Cov.: 41 AF XY: 0.442 AC XY: 321088 AN XY: 725642

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.495

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.360 AC: 54480 AN: 151478 Hom.: 11199 Cov.: 30 AF XY: 0.366 AC XY: 27085 AN XY: 73988

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.331

Alfa AF: 0.404 Hom.: 5493

Bravo AF: 0.339

Asia WGS AF: 0.395 AC: 1365 AN: 3466

EpiCase AF: 0.418

EpiControl AF: 0.409

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.55

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: rs13035; hg19: chr12-21623122; COSMIC: COSV53709917; COSMIC: COSV53709917;