rs17849408

Variant names:

• chr12-21470245-T-C
• rs17849408
• NM_002907.4:c.1899A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002907.4(RECQL):​c.1899A>G​(p.Gln633Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,610,128 control chromosomes in the GnomAD database, including 8,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1051 hom., cov: 28)
  • Exomes 𝑓: 0.095 (7679 hom.)
• Consequence: RECQL NM_002907.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.379
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-21470245-T-C is Benign according to our data. Variant chr12-21470245-T-C is described in ClinVar as Benign. ClinVar VariationId is 506624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.379 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1899A>G	p.Gln633Gln	synonymous_variant	Exon 15 of 15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*1491T>C		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.1899A>G	p.Gln633Gln	synonymous_variant	Exon 15 of 15	2	NM_002907.4	ENSP00000416739.2
RECQL	ENST00000421138.6	c.1899A>G	p.Gln633Gln	synonymous_variant	Exon 16 of 16	1		ENSP00000395449.2
PYROXD1	ENST00000240651.14	c.*1491T>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_024854.5	ENSP00000240651.9
PYROXD1	ENST00000538582.5	c.*1491T>C		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000438505.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16751 AN: 151206 Hom.: 1049 Cov.: 28

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.111 AC: 27488 AN: 247880 AF XY: 0.109

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.317

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0953 AC: 139066 AN: 1458804 Hom.: 7679 Cov.: 41 AF XY: 0.0952 AC XY: 69089 AN XY: 725636

African (AFR) AF: 0.126 AC: 4184 AN: 33292

American (AMR) AF: 0.106 AC: 4718 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3189 AN: 26004

East Asian (EAS) AF: 0.291 AC: 11507 AN: 39588

South Asian (SAS) AF: 0.0997 AC: 8550 AN: 85756

European-Finnish (FIN) AF: 0.101 AC: 5391 AN: 53356

Middle Eastern (MID) AF: 0.110 AC: 632 AN: 5736

European-Non Finnish (NFE) AF: 0.0848 AC: 94164 AN: 1110496

Other (OTH) AF: 0.112 AC: 6731 AN: 60248

GnomAD4 genome AF: 0.111 AC: 16775 AN: 151324 Hom.: 1051 Cov.: 28 AF XY: 0.113 AC XY: 8341 AN XY: 73930

African (AFR) AF: 0.124 AC: 5137 AN: 41320

American (AMR) AF: 0.128 AC: 1939 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3460

East Asian (EAS) AF: 0.308 AC: 1572 AN: 5096

South Asian (SAS) AF: 0.101 AC: 484 AN: 4812

European-Finnish (FIN) AF: 0.0983 AC: 1024 AN: 10422

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0863 AC: 5844 AN: 67738

Other (OTH) AF: 0.122 AC: 256 AN: 2096

Alfa AF: 0.0918 Hom.: 270

Bravo AF: 0.114

Asia WGS AF: 0.180 AC: 625 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Dec 15, 2017

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	-0.86
CADD	Benign	4.3
DANN	Benign	0.84
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17849408; hg19: chr12-21623179; COSMIC: COSV53708718; COSMIC: COSV53708718;