5-7867917-T-C

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.167A>G(p.Lys56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 1,613,950 control chromosomes in the GnomAD database, including 559,506 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.

Frequency

Genomes: 𝑓 0.85 ( 54805 hom., cov: 30)

Exomes 𝑓: 0.83 ( 504701 hom. )

Consequence

FASTKD3
NM_024091.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.480

Publications

48 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=1.2481225E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASTKD3	NM_024091.4 link	c.167A>G	p.Lys56Arg	missense_variant	Exon 2 of 7	ENST00000264669.10	NP_076996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASTKD3	ENST00000264669.10 link	c.167A>G	p.Lys56Arg	missense_variant	Exon 2 of 7	2	NM_024091.4	ENSP00000264669.5

Frequencies

GnomAD3 genomes

AF:

0.847

AC:

128777

AN:

152008

Hom.:

54749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.901

Gnomad AMI

AF:

0.860

Gnomad AMR

AF:

0.853

Gnomad ASJ

AF:

0.800

Gnomad EAS

AF:

0.703

Gnomad SAS

AF:

0.807

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.834

Gnomad OTH

AF:

0.830

GnomAD2 exomes

AF:

0.820

AC:

206128

AN:

251460

AF XY:

0.816

show subpopulations

Gnomad AFR exome

AF:

0.905

Gnomad AMR exome

AF:

0.835

Gnomad ASJ exome

AF:

0.789

Gnomad EAS exome

AF:

0.699

Gnomad FIN exome

AF:

0.821

Gnomad NFE exome

AF:

0.831

Gnomad OTH exome

AF:

0.821

GnomAD4 exome

AF:

0.830

AC:

1213526

AN:

1461822

Hom.:

504701

Cov.:

AF XY:

0.829

AC XY:

602601

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.907

AC:

30348

AN:

33478

American (AMR)

AF:

0.836

AC:

37409

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.790

AC:

20653

AN:

26134

East Asian (EAS)

AF:

0.683

AC:

27126

AN:

39698

South Asian (SAS)

AF:

0.802

AC:

69202

AN:

86256

European-Finnish (FIN)

AF:

0.821

AC:

43881

AN:

53420

Middle Eastern (MID)

AF:

0.802

AC:

4624

AN:

5764

European-Non Finnish (NFE)

AF:

0.837

AC:

930248

AN:

1111956

Other (OTH)

AF:

0.829

AC:

50035

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

12227

24453

36680

48906

61133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21064

42128

63192

84256

105320

<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:

0.847

AC:

128897

AN:

152128

Hom.:

54805

Cov.:

AF XY:

0.845

AC XY:

62846

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.901

AC:

37399

AN:

41508

American (AMR)

AF:

0.854

AC:

13054

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.800

AC:

2774

AN:

3466

East Asian (EAS)

AF:

0.704

AC:

3630

AN:

5158

South Asian (SAS)

AF:

0.807

AC:

3883

AN:

4812

European-Finnish (FIN)

AF:

0.822

AC:

8693

AN:

10574

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.834

AC:

56684

AN:

68006

Other (OTH)

AF:

0.829

AC:

1745

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1002

2004

3005

4007

5009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.832

Hom.:

178941

Bravo

AF:

0.849

TwinsUK

AF:

0.831

AC:

3082

ALSPAC

AF:

0.843

AC:

3247

ESP6500AA

AF:

0.892

AC:

3932

ESP6500EA

AF:

0.825

AC:

7091

ExAC

AF:

0.820

AC:

99559

Asia WGS

AF:

0.757

AC:

2633

AN:

3478

EpiCase

AF:

0.819

EpiControl

AF:

0.816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.32

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.00041

T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.19

T;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

N;.;.

PhyloP100

-0.48

PrimateAI

Benign

0.23

PROVEAN

Benign

0.49

N;N;N

REVEL

Benign

0.019

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.94

T;.;T

Vest4

0.0070

ClinPred

0.0012

GERP RS

0.97

Varity_R

0.028

gMVP

0.043

Mutation Taster

=100/0

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