5-7867917-T-C

Position:

• chr5-7867917-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.167A>G​(p.Lys56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 1,613,950 control chromosomes in the GnomAD database, including 559,506 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.

• Frequency:
  • Genomes: 𝑓 0.85 (54805 hom., cov: 30)
  • Exomes 𝑓: 0.83 (504701 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2481225E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTKD3	NM_024091.4	c.167A>G	p.Lys56Arg	missense_variant	2/7	ENST00000264669.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTKD3	ENST00000264669.10	c.167A>G	p.Lys56Arg	missense_variant	2/7	2	NM_024091.4	P1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128777 AN: 152008 Hom.: 54749 Cov.: 30

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.830

GnomAD3 exomes AF: 0.820 AC: 206128 AN: 251460 Hom.: 84873 AF XY: 0.816 AC XY: 110912 AN XY: 135906

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.699

Gnomad SAS exome AF: 0.799

Gnomad FIN exome AF: 0.821

Gnomad NFE exome AF: 0.831

Gnomad OTH exome AF: 0.821

GnomAD4 exome AF: 0.830 AC: 1213526 AN: 1461822 Hom.: 504701 Cov.: 67 AF XY: 0.829 AC XY: 602601 AN XY: 727218

Gnomad4 AFR exome AF: 0.907

Gnomad4 AMR exome AF: 0.836

Gnomad4 ASJ exome AF: 0.790

Gnomad4 EAS exome AF: 0.683

Gnomad4 SAS exome AF: 0.802

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.837

Gnomad4 OTH exome AF: 0.829

GnomAD4 genome AF: 0.847 AC: 128897 AN: 152128 Hom.: 54805 Cov.: 30 AF XY: 0.845 AC XY: 62846 AN XY: 74352

Gnomad4 AFR AF: 0.901

Gnomad4 AMR AF: 0.854

Gnomad4 ASJ AF: 0.800

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.807

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.829

Alfa AF: 0.828 Hom.: 129133

Bravo AF: 0.849

TwinsUK AF: 0.831 AC: 3082

ALSPAC AF: 0.843 AC: 3247

ESP6500AA AF: 0.892 AC: 3932

ESP6500EA AF: 0.825 AC: 7091

ExAC AF: 0.820 AC: 99559

Asia WGS AF: 0.757 AC: 2633 AN: 3478

EpiCase AF: 0.819

EpiControl AF: 0.816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.32
DANN	Benign	0.24
DEOGEN2	Benign	0.00041	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.8	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.49	N;N;N
REVEL	Benign	0.019
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.94	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.0070
MPC		0.15
ClinPred		0.0012	T
GERP RS		0.97
Varity_R		0.028
gMVP		0.043

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;