NM_002907.4:c.1936dupA

Variant names:

• chr12-21470207-A-AT
• rs1942901642
• NM_002907.4:c.1936dupA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002907.4(RECQL):​c.1936dupA​(p.Ile646AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL NM_002907.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.557

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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00718 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1936dupA	p.Ile646AsnfsTer3	frameshift_variant	Exon 15 of 15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1458dupT		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.1936dupA	p.Ile646AsnfsTer3	frameshift_variant	Exon 15 of 15	2	NM_002907.4	ENSP00000416739.2
RECQL	ENST00000421138.6	c.1936dupA	p.Ile646AsnfsTer3	frameshift_variant	Exon 16 of 16	1		ENSP00000395449.2
PYROXD1	ENST00000240651.14	c.*1458dupT		3_prime_UTR_variant	Exon 12 of 12	1	NM_024854.5	ENSP00000240651.9
PYROXD1	ENST00000538582.5	c.*1458dupT		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000438505.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1459838 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726226

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1936dupA variant, located in coding exon 14 of the RECQL gene, results from a duplication of A at nucleotide position 1936, causing a translational frameshift with a predicted alternate stop codon (p.I646Nfs*3). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

RECQL-related disorder Uncertain:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RECQL c.1936dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile646Asnfs*3). This variant has been reported in an non-smoking individual with lung cancer (Zhang et al. 2021. PubMed ID: 34493867. Table S5). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1942901642; hg19: chr12-21623141;