12-21469761-A-G

Position:

• chr12-21469761-A-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.*433T>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 0.183 in 153,596 control chromosomes in the GnomAD database, including 2,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2586 hom., cov: 31)
  • Exomes 𝑓: 0.17 (45 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.726

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=-0.96).
• BP6: Variant 12-21469761-A-G is Benign according to our data. Variant chr12-21469761-A-G is described in ClinVar as [Benign]. Clinvar id is 1292479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL	NM_002907.4	c.*433T>C		3_prime_UTR_variant	15/15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1007A>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.*1007A>G		3_prime_UTR_variant	12/12	1	NM_024854.5	ENSP00000240651	P1
RECQL	ENST00000444129.7	c.*433T>C		3_prime_UTR_variant	15/15	2	NM_002907.4	ENSP00000416739	P1
PYROXD1	ENST00000538582.5	c.*1007A>G		3_prime_UTR_variant	12/12	2		ENSP00000438505
RECQL	ENST00000421138.6			downstream_gene_variant		1		ENSP00000395449	P1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27629 AN: 150740 Hom.: 2582 Cov.: 31

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.167 AC: 457 AN: 2734 Hom.: 45 Cov.: 0 AF XY: 0.169 AC XY: 274 AN XY: 1626

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.0806

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.183 AC: 27644 AN: 150862 Hom.: 2586 Cov.: 31 AF XY: 0.180 AC XY: 13298 AN XY: 73746

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.0679

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.190

Alfa AF: 0.0563 Hom.: 63

Asia WGS AF: 0.125 AC: 437 AN: 3476

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	Jun 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.7
DANN	Benign	0.37

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: rs1138675; hg19: chr12-21622695;