12-21469888-T-C

Position:

• chr12-21469888-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.*306A>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 0.0353 in 209,530 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (116 hom., cov: 32)
  • Exomes 𝑓: 0.043 (60 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.997

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=-0.92).
• BP6: Variant 12-21469888-T-C is Benign according to our data. Variant chr12-21469888-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1223508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL	NM_002907.4	c.*306A>G		3_prime_UTR_variant	15/15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1134T>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.*1134T>C		3_prime_UTR_variant	12/12	1	NM_024854.5	ENSP00000240651	P1
RECQL	ENST00000444129.7	c.*306A>G		3_prime_UTR_variant	15/15	2	NM_002907.4	ENSP00000416739	P1
RECQL	ENST00000421138.6	c.*306A>G		3_prime_UTR_variant	16/16	1		ENSP00000395449	P1
PYROXD1	ENST00000538582.5	c.*1134T>C		3_prime_UTR_variant	12/12	2		ENSP00000438505

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4912 AN: 152010 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0583

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0502

GnomAD4 exome AF: 0.0433 AC: 2483 AN: 57402 Hom.: 60 Cov.: 0 AF XY: 0.0435 AC XY: 1358 AN XY: 31234

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.000456

Gnomad4 SAS exome AF: 0.0362

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0493

Gnomad4 OTH exome AF: 0.0443

GnomAD4 genome AF: 0.0322 AC: 4906 AN: 152128 Hom.: 116 Cov.: 32 AF XY: 0.0308 AC XY: 2290 AN XY: 74390

Gnomad4 AFR AF: 0.00855

Gnomad4 AMR AF: 0.0392

Gnomad4 ASJ AF: 0.0583

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0353 Hom.: 16

Bravo AF: 0.0331

Asia WGS AF: 0.0150 AC: 52 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.69

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: rs71582885; hg19: chr12-21622822;