rs6500

Variant names:

• chr12-21471035-A-G
• rs6500
• NM_002907.4:c.1731T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002907.4(RECQL):​c.1731T>C​(p.Asn577Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.096 in 1,599,836 control chromosomes in the GnomAD database, including 8,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1074 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7474 hom.)
• Consequence: RECQL NM_002907.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.208
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-21471035-A-G is Benign according to our data. Variant chr12-21471035-A-G is described in ClinVar as Benign. ClinVar VariationId is 506623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL	NM_002907.4	c.1731T>C	p.Asn577Asn	synonymous_variant	Exon 14 of 15	ENST00000444129.7	NP_002898.2
PYROXD1	NM_024854.5	c.*2281A>G		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.1731T>C	p.Asn577Asn	synonymous_variant	Exon 14 of 15	2	NM_002907.4	ENSP00000416739.2
RECQL	ENST00000421138.6	c.1731T>C	p.Asn577Asn	synonymous_variant	Exon 15 of 16	1		ENSP00000395449.2
PYROXD1	ENST00000240651.14	c.*2281A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_024854.5	ENSP00000240651.9

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16956 AN: 151952 Hom.: 1072 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.108 AC: 25832 AN: 239658 AF XY: 0.107

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0960

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.0830

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0943 AC: 136591 AN: 1447766 Hom.: 7474 Cov.: 31 AF XY: 0.0942 AC XY: 67870 AN XY: 720330

African (AFR) AF: 0.123 AC: 3985 AN: 32444

American (AMR) AF: 0.102 AC: 4295 AN: 42188

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3101 AN: 25724

East Asian (EAS) AF: 0.285 AC: 10892 AN: 38258

South Asian (SAS) AF: 0.0972 AC: 8188 AN: 84240

European-Finnish (FIN) AF: 0.100 AC: 5337 AN: 53112

Middle Eastern (MID) AF: 0.108 AC: 616 AN: 5698

European-Non Finnish (NFE) AF: 0.0846 AC: 93586 AN: 1106478

Other (OTH) AF: 0.111 AC: 6591 AN: 59624

GnomAD4 genome AF: 0.112 AC: 16980 AN: 152070 Hom.: 1074 Cov.: 32 AF XY: 0.114 AC XY: 8448 AN XY: 74342

African (AFR) AF: 0.125 AC: 5208 AN: 41524

American (AMR) AF: 0.129 AC: 1958 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 442 AN: 3468

East Asian (EAS) AF: 0.311 AC: 1603 AN: 5154

South Asian (SAS) AF: 0.101 AC: 489 AN: 4822

European-Finnish (FIN) AF: 0.100 AC: 1061 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0866 AC: 5883 AN: 67958

Other (OTH) AF: 0.122 AC: 258 AN: 2110

Alfa AF: 0.101 Hom.: 591

Bravo AF: 0.114

Asia WGS AF: 0.182 AC: 634 AN: 3474

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	-0.53
CADD	Benign	6.5
DANN	Benign	0.81
PhyloP100		0.21
Mutation Taster		=93/7	polymorphism (auto)

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: rs6500; hg19: chr12-21623969; COSMIC: COSV53708721; COSMIC: COSV53708721;