rs11046076

Variant names:

• chr12-21471375-A-T
• rs11046076
• NM_002907.4:c.1667+53T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002907.4(RECQL):​c.1667+53T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (11225 hom., cov: 25)
  • Exomes 𝑓: 0.61 (123009 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL NM_002907.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600
• Publications: 4 publications found

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]

PYROXD1 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-21471375-A-T is Benign according to our data. Variant chr12-21471375-A-T is described in ClinVar as Benign. ClinVar VariationId is 679695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1667+53T>A		intron_variant	Intron 13 of 14	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*2621A>T		downstream_gene_variant		ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL	ENST00000444129.7	c.1667+53T>A		intron_variant	Intron 13 of 14	2	NM_002907.4	ENSP00000416739.2
RECQL	ENST00000421138.6	c.1667+53T>A		intron_variant	Intron 14 of 15	1		ENSP00000395449.2
PYROXD1	ENST00000240651.14	c.*2621A>T		downstream_gene_variant		1	NM_024854.5	ENSP00000240651.9

Frequencies

GnomAD3 genomes AF: 0.549 AC: 54687 AN: 99574 Hom.: 11228 Cov.: 25

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.512

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.528

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.612 AC: 560033 AN: 914676 Hom.: 123009 Cov.: 14 AF XY: 0.614 AC XY: 280746 AN XY: 457500

African (AFR) AF: 0.269 AC: 3677 AN: 13670

American (AMR) AF: 0.624 AC: 14989 AN: 24036

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 9521 AN: 16340

East Asian (EAS) AF: 0.567 AC: 16410 AN: 28964

South Asian (SAS) AF: 0.644 AC: 36265 AN: 56304

European-Finnish (FIN) AF: 0.659 AC: 26414 AN: 40078

Middle Eastern (MID) AF: 0.501 AC: 1457 AN: 2908

European-Non Finnish (NFE) AF: 0.618 AC: 429696 AN: 695668

Other (OTH) AF: 0.589 AC: 21604 AN: 36708

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.549 AC: 54687 AN: 99638 Hom.: 11225 Cov.: 25 AF XY: 0.554 AC XY: 27192 AN XY: 49068

African (AFR) AF: 0.300 AC: 6114 AN: 20362

American (AMR) AF: 0.580 AC: 6064 AN: 10450

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 1480 AN: 2496

East Asian (EAS) AF: 0.560 AC: 2310 AN: 4124

South Asian (SAS) AF: 0.648 AC: 2411 AN: 3718

European-Finnish (FIN) AF: 0.659 AC: 5474 AN: 8304

Middle Eastern (MID) AF: 0.507 AC: 76 AN: 150

European-Non Finnish (NFE) AF: 0.617 AC: 29717 AN: 48156

Other (OTH) AF: 0.527 AC: 694 AN: 1316

Alfa AF: 0.368 Hom.: 1040

Bravo AF: 0.340

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.15
DANN	Benign	0.42
PhyloP100		0.0060
Mutation Taster		=6/94	disease causing (long InDel)

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

Other links and lift over

dbSNP: rs11046076; hg19: chr12-21624309; COSMIC: COSV53710106; COSMIC: COSV53710106;