NM_024091.4:c.167A>G

Variant names:

• chr5-7867917-T-C
• rs2966952
• NM_024091.4:c.167A>G

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 48 publications found

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]

MTRR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblE

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024091.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD3	NM_024091.4	MANE Select	c.167A>G	p.Lys56Arg	missense	Exon 2 of 7	NP_076996.2
	FASTKD3	NR_036553.2		n.53+1062A>G		intron	N/A
	FASTKD3	NR_073608.2		n.53+1062A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD3	ENST00000264669.10	TSL:2 MANE Select	c.167A>G	p.Lys56Arg	missense	Exon 2 of 7	ENSP00000264669.5
	FASTKD3	ENST00000507036.1	TSL:1	n.167A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000421798.1
	FASTKD3	ENST00000282110.8	TSL:1	n.32+1062A>G		intron	N/A

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

GnomAD2 exomes AF: 0.820 AC: 206128 AN: 251460 AF XY: 0.816

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 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

African (AFR) AF: 0.907 AC: 30348 AN: 33478

American (AMR) AF: 0.836 AC: 37409 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 20653 AN: 26134

East Asian (EAS) AF: 0.683 AC: 27126 AN: 39698

South Asian (SAS) AF: 0.802 AC: 69202 AN: 86256

European-Finnish (FIN) AF: 0.821 AC: 43881 AN: 53420

Middle Eastern (MID) AF: 0.802 AC: 4624 AN: 5764

European-Non Finnish (NFE) AF: 0.837 AC: 930248 AN: 1111956

Other (OTH) AF: 0.829 AC: 50035 AN: 60392

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

African (AFR) AF: 0.901 AC: 37399 AN: 41508

American (AMR) AF: 0.854 AC: 13054 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2774 AN: 3466

East Asian (EAS) AF: 0.704 AC: 3630 AN: 5158

South Asian (SAS) AF: 0.807 AC: 3883 AN: 4812

European-Finnish (FIN) AF: 0.822 AC: 8693 AN: 10574

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56684 AN: 68006

Other (OTH) AF: 0.829 AC: 1745 AN: 2106

Alfa AF: 0.832 Hom.: 178941

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 v4.9

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
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.48
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	0.94	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2966952; hg19: chr5-7868030; COSMIC: COSV107280110; COSMIC: COSV107280110;