5-7866709-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024091.4(FASTKD3):c.1375G>C(p.Glu459Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,612,378 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E459G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (7 hom.)
• Consequence: FASTKD3 NM_024091.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.44

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049411952).
• BP6: Variant 5-7866709-C-G is Benign according to our data. Variant chr5-7866709-C-G is described in ClinVar as [Benign]. Clinvar id is 790563.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-7866709-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD3	NM_024091.4	c.1375G>C	p.Glu459Gln	missense_variant	2/7	ENST00000264669.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD3	ENST00000264669.10	c.1375G>C	p.Glu459Gln	missense_variant	2/7	2	NM_024091.4	P1

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 614 AN: 152152 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00105 AC: 261 AN: 249676 Hom.: 2 AF XY: 0.000727 AC XY: 98 AN XY: 134836

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000554

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: 0.00000883

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000411 AC: 600 AN: 1460106 Hom.: 7 Cov.: 31 AF XY: 0.000318 AC XY: 231 AN XY: 726086

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.000562

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: 0.00000810

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152272 Hom.: 8 Cov.: 33 AF XY: 0.00389 AC XY: 290 AN XY: 74472

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000673 Hom.: 2

Bravo AF: 0.00474

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00135 AC: 164

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.088
Sift	Benign	0.35	T
Sift4G	Benign	0.27	T
Polyphen		0.50	P
Vest4		0.12
MVP		0.62
MPC		0.32
ClinPred		0.029	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.42

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: rs115086471; hg19: chr5-7866822;