Genetic Variant NM_002907.4:c.1899A>G (chr12-21470245-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002907.4(RECQL):c.1899A>G(p.Gln633Gln) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.379

Publications

5 publications found

Variant links:

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]

RECQL links:

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)

PYROXD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL	NM_002907.4	MANE Select	c.1899A>G	p.Gln633Gln	synonymous	Exon 15 of 15	NP_002898.2
PYROXD1	NM_024854.5	MANE Select	c.*1491T>C		3_prime_UTR	Exon 12 of 12	NP_079130.2	Q8WU10-1
RECQL	NM_032941.3		c.1899A>G	p.Gln633Gln	synonymous	Exon 16 of 16	NP_116559.1	P46063

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL	ENST00000444129.7	TSL:2 MANE Select	c.1899A>G	p.Gln633Gln	synonymous	Exon 15 of 15	ENSP00000416739.2	P46063
RECQL	ENST00000421138.6	TSL:1	c.1899A>G	p.Gln633Gln	synonymous	Exon 16 of 16	ENSP00000395449.2	P46063
PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.*1491T>C		3_prime_UTR	Exon 12 of 12	ENSP00000240651.9	Q8WU10-1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16751

AN:

151206

Hom.:

1049

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.111

AC:

27488

AN:

247880

AF XY:

0.109

show subpopulations

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 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.:

AF XY:

0.0952

AC XY:

69089

AN XY:

725636

show subpopulations

African (AFR)

AF:

0.126

AC:

4184

AN:

33292

American (AMR)

AF:

0.106

AC:

4718

AN:

44328

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3189

AN:

26004

East Asian (EAS)

AF:

0.291

AC:

11507

AN:

39588

South Asian (SAS)

AF:

0.0997

AC:

8550

AN:

85756

European-Finnish (FIN)

AF:

0.101

AC:

5391

AN:

53356

Middle Eastern (MID)

AF:

0.110

AC:

632

AN:

5736

European-Non Finnish (NFE)

AF:

0.0848

AC:

94164

AN:

1110496

Other (OTH)

AF:

0.112

AC:

6731

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

6533

13065

19598

26130

32663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3644

7288

10932

14576

18220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.111

AC:

16775

AN:

151324

Hom.:

1051

Cov.:

AF XY:

0.113

AC XY:

8341

AN XY:

73930

show subpopulations

African (AFR)

AF:

0.124

AC:

5137

AN:

41320

American (AMR)

AF:

0.128

AC:

1939

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

441

AN:

3460

East Asian (EAS)

AF:

0.308

AC:

1572

AN:

5096

South Asian (SAS)

AF:

0.101

AC:

484

AN:

4812

European-Finnish (FIN)

AF:

0.0983

AC:

1024

AN:

10422

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0863

AC:

5844

AN:

67738

Other (OTH)

AF:

0.122

AC:

256

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

650

1300

1950

2600

3250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0918

Hom.:

270

Bravo

AF:

0.114

Asia WGS

AF:

0.180

AC:

625

AN:

3466

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.3

(source)

DANN

Benign

0.84

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over