rs2966952

Positions:

• chr5-7867917-T-A
• chr5-7867917-T-C
• chr5-7867917-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024091.4(FASTKD3):​c.167A>T​(p.Lys56Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K56R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: FASTKD3 NM_024091.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.480

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06618059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD3	NM_024091.4	c.167A>T	p.Lys56Ile	missense_variant	2/7	ENST00000264669.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD3	ENST00000264669.10	c.167A>T	p.Lys56Ile	missense_variant	2/7	2	NM_024091.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.0027	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.41	T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.037	D;T;T
Sift4G	Benign	0.13	T;.;D
Polyphen		0.090	B;.;.
Vest4		0.21
MutPred		0.46		Loss of methylation at K56 (P = 0.0011);Loss of methylation at K56 (P = 0.0011);.;
MVP		0.22
MPC		0.34
ClinPred		0.038	T
GERP RS		0.97
Varity_R		0.11
gMVP		0.14

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: rs2966952; hg19: chr5-7868030;