Genetic Variant FASTKD3:p.Leu432Leu (chr5-7866788-C-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_024091.4(FASTKD3):c.1296G>T(p.Leu432Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,138 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 10 hom. )

Consequence

FASTKD3
NM_024091.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.199

Publications

3 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

MTRR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 5-7866788-C-A is Benign according to our data. Variant chr5-7866788-C-A is described in ClinVar as Benign. ClinVar VariationId is 771859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.199 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024091.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FASTKD3	NM_024091.4	MANE Select	c.1296G>T	p.Leu432Leu	synonymous	Exon 2 of 7	NP_076996.2
FASTKD3	NR_036553.2		n.54-805G>T		intron	N/A
FASTKD3	NR_073608.2		n.54-805G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FASTKD3	ENST00000264669.10	TSL:2 MANE Select	c.1296G>T	p.Leu432Leu	synonymous	Exon 2 of 7	ENSP00000264669.5	Q14CZ7
FASTKD3	ENST00000507036.1	TSL:1	n.1296G>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000421798.1	D6RAR6
FASTKD3	ENST00000511261.5	TSL:1	n.*559G>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000424568.1	D6RB04

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

384

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00269

AC:

675

AN:

251336

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00410

AC:

5987

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

2906

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33478

American (AMR)

AF:

0.00168

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86246

European-Finnish (FIN)

AF:

0.00283

AC:

151

AN:

53414

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00489

AC:

5438

AN:

1111996

Other (OTH)

AF:

0.00301

AC:

182

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

302

605

907

1210

1512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00252

AC:

384

AN:

152282

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41560

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00346

Hom.:

Bravo

AF:

0.00249

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00379

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.23

(source)

DANN

Benign

0.71

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over