rs16879259

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024091.4(FASTKD3):c.1376A>G(p.Glu459Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 1,611,430 control chromosomes in the GnomAD database, including 2,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E459Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.058 ( 405 hom., cov: 33)

Exomes 𝑓: 0.039 ( 2062 hom. )

Consequence

FASTKD3
NM_024091.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

14 publications found

Variant links:

Genes affected

FASTKD3 (HGNC:28758): (FAST kinase domains 3) This gene encodes a member of a small family of Fas-activated serine/threonine kinase domain (FASTKD) containing proteins that share an amino terminal mitochondrial targeting domain and multiple carboxy terminal FAST domains as well as a putative RNA-binding RAP domain. The members of this family are ubiquitously expressed and are generally most abundant in mitochondria-enriched tissues such as heart, skeletal muscle and brown-adipose tissue. Some members of this protein family may play a role in apoptosis. The protein encoded by this gene interacts with components of the mitochondrial respiratory and translation networks. A pseudogene of this gene is also present on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

FASTKD3 links:

MTRR (HGNC:7473): (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MTRR Gene-Disease associations (from GenCC):

methylcobalamin deficiency type cblE
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

MTRR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010035336).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD3	NM_024091.4 link	c.1376A>G	p.Glu459Gly	missense_variant	Exon 2 of 7	ENST00000264669.10	NP_076996.2	Q14CZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASTKD3	ENST00000264669.10 link	c.1376A>G	p.Glu459Gly	missense_variant	Exon 2 of 7	2	NM_024091.4	ENSP00000264669.5		Q14CZ7

Frequencies

GnomAD3 genomes

AF:

0.0578

AC:

8789

AN:

152174

Hom.:

402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0728

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0937

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.213

Gnomad SAS

AF:

0.0372

Gnomad FIN

AF:

0.0701

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0488

GnomAD2 exomes

AF:

0.0654

AC:

16282

AN:

248950

AF XY:

0.0586

show subpopulations

Gnomad AFR exome

AF:

0.0746

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.0682

Gnomad NFE exome

AF:

0.0312

Gnomad OTH exome

AF:

0.0472

GnomAD4 exome

AF:

0.0392

AC:

57130

AN:

1459138

Hom.:

2062

Cov.:

AF XY:

0.0385

AC XY:

27909

AN XY:

725460

show subpopulations

African (AFR)

AF:

0.0710

AC:

2364

AN:

33318

American (AMR)

AF:

0.138

AC:

6135

AN:

44338

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

354

AN:

26074

East Asian (EAS)

AF:

0.191

AC:

7591

AN:

39670

South Asian (SAS)

AF:

0.0339

AC:

2887

AN:

85214

European-Finnish (FIN)

AF:

0.0663

AC:

3540

AN:

53404

Middle Eastern (MID)

AF:

0.00660

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0285

AC:

31687

AN:

1111062

Other (OTH)

AF:

0.0420

AC:

2534

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2850

5701

8551

11402

14252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1344

2688

4032

5376

6720

<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:

0.0578

AC:

8801

AN:

152292

Hom.:

405

Cov.:

AF XY:

0.0601

AC XY:

4474

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0729

AC:

3031

AN:

41556

American (AMR)

AF:

0.0937

AC:

1434

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.213

AC:

1103

AN:

5178

South Asian (SAS)

AF:

0.0371

AC:

179

AN:

4830

European-Finnish (FIN)

AF:

0.0701

AC:

744

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0315

AC:

2140

AN:

68022

Other (OTH)

AF:

0.0473

AC:

100

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

417

834

1252

1669

2086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0413

Hom.:

459

Bravo

AF:

0.0607

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0719

AC:

317

ESP6500EA

AF:

0.0273

AC:

235

ExAC

AF:

0.0617

AC:

7490

Asia WGS

AF:

0.123

AC:

426

AN:

3478

EpiCase

AF:

0.0254

EpiControl

AF:

0.0255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.059

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

2.3

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.083

Sift

Benign

0.20

Sift4G

Benign

0.099

Polyphen

0.033

Vest4

0.041

MPC

0.24

ClinPred

0.015

GERP RS

-3.0

Varity_R

0.14

gMVP

0.52

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over