5-7867437-C-A

Variant summary

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

The NM_024091.4(FASTKD3):c.647G>T(p.Arg216Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FASTKD3 NM_024091.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.948

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=0.03951943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD3	NM_024091.4	c.647G>T	p.Arg216Leu	missense_variant	2/7	ENST00000264669.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD3	ENST00000264669.10	c.647G>T	p.Arg216Leu	missense_variant	2/7	2	NM_024091.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250822 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135540

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 69 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.647G>T (p.R216L) alteration is located in exon 2 (coding exon 1) of the FASTKD3 gene. This alteration results from a G to T substitution at nucleotide position 647, causing the arginine (R) at amino acid position 216 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.37
Dann	Benign	0.81
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.062
Sift	Benign	0.29	T;T
Sift4G	Benign	0.28	T;.
Polyphen		0.0	B;.
Vest4		0.14
MVP		0.32
MPC		0.26
ClinPred		0.029	T
GERP RS		-9.5
Varity_R		0.048
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150488459; hg19: chr5-7867550;