12-21469993-T-C

Variant names:

• chr12-21469993-T-C
• rs74067191
• NM_002907.4:c.*201A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002907.4(RECQL):​c.*201A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 660,224 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (96 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (33 hom.)
• Consequence: RECQL NM_002907.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.309
• 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 12-21469993-T-C is Benign according to our data. Variant chr12-21469993-T-C is described in ClinVar as Benign. ClinVar VariationId is 1237151.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

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.*201A>G		3_prime_UTR	Exon 15 of 15	NP_002898.2
	PYROXD1	NM_024854.5	MANE Select	c.*1239T>C		3_prime_UTR	Exon 12 of 12	NP_079130.2	Q8WU10-1
	RECQL	NM_032941.3		c.*201A>G		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.*201A>G		3_prime_UTR	Exon 15 of 15	ENSP00000416739.2	P46063
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.*1239T>C		3_prime_UTR	Exon 12 of 12	ENSP00000240651.9	Q8WU10-1
	RECQL	ENST00000421138.6	TSL:1	c.*201A>G		3_prime_UTR	Exon 16 of 16	ENSP00000395449.2	P46063

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3089 AN: 152026 Hom.: 97 Cov.: 31

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00814

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.00306 AC: 1555 AN: 508080 Hom.: 33 Cov.: 8 AF XY: 0.00286 AC XY: 734 AN XY: 256864

African (AFR) AF: 0.0690 AC: 765 AN: 11090

American (AMR) AF: 0.00704 AC: 73 AN: 10364

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 348 AN: 10722

East Asian (EAS) AF: 0.00 AC: 0 AN: 22102

South Asian (SAS) AF: 0.000333 AC: 8 AN: 24042

European-Finnish (FIN) AF: 0.000254 AC: 7 AN: 27542

Middle Eastern (MID) AF: 0.00620 AC: 11 AN: 1774

European-Non Finnish (NFE) AF: 0.000391 AC: 147 AN: 375790

Other (OTH) AF: 0.00795 AC: 196 AN: 24654

GnomAD4 genome AF: 0.0203 AC: 3093 AN: 152144 Hom.: 96 Cov.: 31 AF XY: 0.0196 AC XY: 1459 AN XY: 74398

African (AFR) AF: 0.0666 AC: 2765 AN: 41516

American (AMR) AF: 0.00812 AC: 124 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67968

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0182 Hom.: 7

Bravo AF: 0.0234

Asia WGS AF: 0.00579 AC: 21 AN: 3466

ClinVar

ClinVar submissions

Significance: 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	4.6
DANN	Benign	0.66
PhyloP100		0.31
Mutation Taster		=100/0	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: rs74067191; hg19: chr12-21622927;