rs1046012

Variant names:

• chr5-7859410-A-G
• rs1046012
• ENST00000282110.8:n.608T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-7859410-A-G
• chr5-7859410-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000282110.8(FASTKD3):​n.608T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,429,400 control chromosomes in the GnomAD database, including 71,784 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 0.28 (6339 hom., cov: 33)
  • Exomes 𝑓: 0.31 (65445 hom.)
• Consequence: FASTKD3 ENST00000282110.8 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 13 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 (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000282110.8. 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.*25T>C		3_prime_UTR	Exon 7 of 7	NP_076996.2
	FASTKD3	NR_036553.2		n.629T>C		non_coding_transcript_exon	Exon 6 of 6
	FASTKD3	NR_073608.2		n.750T>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD3	ENST00000282110.8	TSL:1	n.608T>C		non_coding_transcript_exon	Exon 6 of 6
	FASTKD3	ENST00000507036.1	TSL:1	n.*308T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000421798.1
	FASTKD3	ENST00000511261.5	TSL:1	n.*1277T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000424568.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42452 AN: 151984 Hom.: 6330 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.281

GnomAD2 exomes AF: 0.262 AC: 56050 AN: 213678 AF XY: 0.265

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.310 AC: 395794 AN: 1277298 Hom.: 65445 Cov.: 17 AF XY: 0.307 AC XY: 196270 AN XY: 639294

African (AFR) AF: 0.232 AC: 6592 AN: 28380

American (AMR) AF: 0.158 AC: 5522 AN: 34914

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 8419 AN: 23358

East Asian (EAS) AF: 0.0326 AC: 1238 AN: 37980

South Asian (SAS) AF: 0.173 AC: 12880 AN: 74646

European-Finnish (FIN) AF: 0.289 AC: 15116 AN: 52296

Middle Eastern (MID) AF: 0.299 AC: 1581 AN: 5284

European-Non Finnish (NFE) AF: 0.339 AC: 328202 AN: 966784

Other (OTH) AF: 0.303 AC: 16244 AN: 53656

GnomAD4 genome AF: 0.279 AC: 42494 AN: 152102 Hom.: 6339 Cov.: 33 AF XY: 0.273 AC XY: 20326 AN XY: 74384

African (AFR) AF: 0.237 AC: 9849 AN: 41494

American (AMR) AF: 0.218 AC: 3325 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1279 AN: 3472

East Asian (EAS) AF: 0.0503 AC: 261 AN: 5188

South Asian (SAS) AF: 0.167 AC: 806 AN: 4824

European-Finnish (FIN) AF: 0.290 AC: 3064 AN: 10574

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22881 AN: 67962

Other (OTH) AF: 0.280 AC: 590 AN: 2104

Alfa AF: 0.325 Hom.: 8563

Bravo AF: 0.273

Asia WGS AF: 0.120 AC: 418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.60
PhyloP100		1.4
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: rs1046012; hg19: chr5-7859523; COSMIC: COSV107280112; COSMIC: COSV107280112;