chr12-21469812-C-T

Variant names:

• chr12-21469812-C-T
• rs148073000
• NM_002907.4:c.*382G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002907.4(RECQL):​c.*382G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00521 in 164,602 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0750
• Publications: 0 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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-21469812-C-T is Benign according to our data. Variant chr12-21469812-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1182600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00556 (844/151702) while in subpopulation AFR AF = 0.0157 (649/41334). AF 95% confidence interval is 0.0147. There are 7 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002907.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL	NM_002907.4	MANE Select	c.*382G>A		3_prime_UTR	Exon 15 of 15	NP_002898.2
	PYROXD1	NM_024854.5	MANE Select	c.*1058C>T		3_prime_UTR	Exon 12 of 12	NP_079130.2	Q8WU10-1
	RECQL	NM_032941.3		c.*382G>A		3_prime_UTR	Exon 16 of 16	NP_116559.1	P46063

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL	ENST00000444129.7	TSL:2 MANE Select	c.*382G>A		3_prime_UTR	Exon 15 of 15	ENSP00000416739.2	P46063
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.*1058C>T		3_prime_UTR	Exon 12 of 12	ENSP00000240651.9	Q8WU10-1
	RECQL	ENST00000421138.6	TSL:1	c.*382G>A		3_prime_UTR	Exon 16 of 16	ENSP00000395449.2	P46063

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 842 AN: 151582 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00283

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00577

GnomAD4 exome AF: 0.00101 AC: 13 AN: 12900 Hom.: 0 Cov.: 0 AF XY: 0.00112 AC XY: 8 AN XY: 7172

African (AFR) AF: 0.0161 AC: 1 AN: 62

American (AMR) AF: 0.00455 AC: 5 AN: 1098

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 5 AN: 122

East Asian (EAS) AF: 0.00 AC: 0 AN: 240

South Asian (SAS) AF: 0.00 AC: 0 AN: 1500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.000232 AC: 2 AN: 8630

Other (OTH) AF: 0.00 AC: 0 AN: 538

GnomAD4 genome AF: 0.00556 AC: 844 AN: 151702 Hom.: 7 Cov.: 31 AF XY: 0.00558 AC XY: 414 AN XY: 74128

African (AFR) AF: 0.0157 AC: 649 AN: 41334

American (AMR) AF: 0.00283 AC: 43 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67914

Other (OTH) AF: 0.00571 AC: 12 AN: 2102

Alfa AF: 0.00493 Hom.: 0

Bravo AF: 0.00603

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.71
PhyloP100		0.075
Mutation Taster		=100/0	polymorphism

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: rs148073000; hg19: chr12-21622746;