rs6500

Positions:

• chr12-21471035-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002907.4(RECQL):​c.1731T>C​(p.Asn577=) 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:2
• Conservation: PhyloP100: 0.208

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 -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 id 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/exons	MANE	UniProt
RECQL	NM_002907.4	c.1731T>C	p.Asn577=	synonymous_variant	14/15	ENST00000444129.7
PYROXD1	NM_024854.5	c.*2281A>G		3_prime_UTR_variant	12/12	ENST00000240651.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL	ENST00000444129.7	c.1731T>C	p.Asn577=	synonymous_variant	14/15	2	NM_002907.4	P1
RECQL	ENST00000421138.6	c.1731T>C	p.Asn577=	synonymous_variant	15/16	1		P1
PYROXD1	ENST00000240651.14	c.*2281A>G		3_prime_UTR_variant	12/12	1	NM_024854.5	P1

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

GnomAD3 exomes AF: 0.108 AC: 25832 AN: 239658 Hom.: 1876 AF XY: 0.107 AC XY: 13894 AN XY: 130206

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 SAS exome AF: 0.0942

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

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.285

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0846

Gnomad4 OTH exome AF: 0.111

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

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0866

Gnomad4 OTH AF: 0.122

Alfa AF: 0.0950 Hom.: 337

Bravo AF: 0.114

Asia WGS AF: 0.182 AC: 634 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.5
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

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