rs326118

Positions:

• chr5-7868430-T-G

Variant summary

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

The NM_024091.4(FASTKD3):​c.-113-234A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,046 control chromosomes in the GnomAD database, including 4,643 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4643 hom., cov: 33)
• Consequence: FASTKD3 NM_024091.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48

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 (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASTKD3	NM_024091.4	c.-113-234A>C		intron_variant		ENST00000264669.10	NP_076996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASTKD3	ENST00000264669.10	c.-113-234A>C		intron_variant		2	NM_024091.4	ENSP00000264669	P1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32109 AN: 151928 Hom.: 4629 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0751

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.202

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 32180 AN: 152046 Hom.: 4643 Cov.: 33 AF XY: 0.209 AC XY: 15515 AN XY: 74326

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0751

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.204

Alfa AF: 0.167 Hom.: 1068

Bravo AF: 0.237

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.68

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: rs326118; hg19: chr5-7868543;