rs17849408

Positions:

• chr12-21470245-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002907.4(RECQL):​c.1899A>G​(p.Gln633=) 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

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 -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 id 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/exons	MANE	UniProt
RECQL	NM_002907.4	c.1899A>G	p.Gln633=	synonymous_variant	15/15	ENST00000444129.7
PYROXD1	NM_024854.5	c.*1491T>C		3_prime_UTR_variant	12/12	ENST00000240651.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL	ENST00000444129.7	c.1899A>G	p.Gln633=	synonymous_variant	15/15	2	NM_002907.4	P1
RECQL	ENST00000421138.6	c.1899A>G	p.Gln633=	synonymous_variant	16/16	1		P1
PYROXD1	ENST00000240651.14	c.*1491T>C		3_prime_UTR_variant	12/12	1	NM_024854.5	P1
PYROXD1	ENST00000538582.5	c.*1491T>C		3_prime_UTR_variant	12/12	2

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

GnomAD3 exomes AF: 0.111 AC: 27488 AN: 247880 Hom.: 1800 AF XY: 0.109 AC XY: 14653 AN XY: 134068

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 SAS exome AF: 0.0973

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

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.0997

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0848

Gnomad4 OTH exome AF: 0.112

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

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0983

Gnomad4 NFE AF: 0.0863

Gnomad4 OTH AF: 0.122

Alfa AF: 0.0947 Hom.: 269

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2017

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17849408; hg19: chr12-21623179; COSMIC: COSV53708718; COSMIC: COSV53708718;