5-7864419-T-C

Variant names:

• chr5-7864419-T-C
• rs16879248
• NM_024091.4:c.1525-1422A>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.1525-1422A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0404 in 152,192 control chromosomes in the GnomAD database, including 276 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 0.040 (276 hom., cov: 33)
• Consequence: FASTKD3 NM_024091.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 4 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD3	NM_024091.4	MANE Select	c.1525-1422A>G		intron	N/A	NP_076996.2
	FASTKD3	NR_036553.2		n.140-1422A>G		intron	N/A
	FASTKD3	NR_073608.2		n.140-1422A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASTKD3	ENST00000264669.10	TSL:2 MANE Select	c.1525-1422A>G		intron	N/A	ENSP00000264669.5	Q14CZ7
	FASTKD3	ENST00000282110.8	TSL:1	n.119-1422A>G		intron	N/A
	FASTKD3	ENST00000507036.1	TSL:1	n.1525-1422A>G		intron	N/A	ENSP00000421798.1	D6RAR6

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6148 AN: 152074 Hom.: 275 Cov.: 33

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0872

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0368

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

GnomAD4 genome AF: 0.0404 AC: 6154 AN: 152192 Hom.: 276 Cov.: 33 AF XY: 0.0438 AC XY: 3257 AN XY: 74426

African (AFR) AF: 0.0128 AC: 533 AN: 41550

American (AMR) AF: 0.0872 AC: 1334 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1096 AN: 5174

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4820

European-Finnish (FIN) AF: 0.0705 AC: 744 AN: 10558

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0312 AC: 2124 AN: 68004

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0354 Hom.: 46

Bravo AF: 0.0408

Asia WGS AF: 0.120 AC: 414 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.29
PhyloP100		-0.0010
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: rs16879248; hg19: chr5-7864532;