rs16879259

Positions:

• chr5-7866708-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E459Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (405 hom., cov: 33)
  • Exomes 𝑓: 0.039 (2062 hom.)
• Consequence: FASTKD3 NM_024091.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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]

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
FASTKD3	NM_024091.4	c.1376A>G	p.Glu459Gly	missense_variant	2/7	ENST00000264669.10	NP_076996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASTKD3	ENST00000264669.10	c.1376A>G	p.Glu459Gly	missense_variant	2/7	2	NM_024091.4	ENSP00000264669	P1

Frequencies

GnomAD3 genomes AF: 0.0578 AC: 8789 AN: 152174 Hom.: 402 Cov.: 33

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

GnomAD3 exomes AF: 0.0654 AC: 16282 AN: 248950 Hom.: 932 AF XY: 0.0586 AC XY: 7874 AN XY: 134354

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 SAS exome AF: 0.0334

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.: 31 AF XY: 0.0385 AC XY: 27909 AN XY: 725460

Gnomad4 AFR exome AF: 0.0710

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.0663

Gnomad4 NFE exome AF: 0.0285

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0578 AC: 8801 AN: 152292 Hom.: 405 Cov.: 33 AF XY: 0.0601 AC XY: 4474 AN XY: 74468

Gnomad4 AFR AF: 0.0729

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.0701

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0394 Hom.: 180

Bravo AF: 0.0607

TwinsUK AF: 0.0262 AC: 97

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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.083
Sift	Benign	0.20	T
Sift4G	Benign	0.099	T
Polyphen		0.033	B
Vest4		0.041
MPC		0.24
ClinPred		0.015	T
GERP RS		-3.0
Varity_R		0.14
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs16879259; hg19: chr5-7866821; COSMIC: COSV99241335; COSMIC: COSV99241335;