NM_177478.2:c.101C>T

Variant names:

• chr5-121852064-C-T
• rs1398561223
• NM_177478.2:c.101C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177478.2(FTMT):​c.101C>T​(p.Pro34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,590,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P34Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FTMT NM_177478.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 1 publications found

Genes affected

FTMT (HGNC:17345): (ferritin mitochondrial) Predicted to enable ferric iron binding activity and ferrous iron binding activity. Involved in several processes, including cellular iron ion homeostasis; positive regulation of aconitate hydratase activity; and positive regulation of succinate dehydrogenase activity. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LOC105379149 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12030789).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177478.2. 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
	FTMT	NM_177478.2	MANE Select	c.101C>T	p.Pro34Leu	missense	Exon 1 of 1	NP_803431.1	Q8N4E7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTMT	ENST00000321339.3	TSL:6 MANE Select	c.101C>T	p.Pro34Leu	missense	Exon 1 of 1	ENSP00000313691.1	Q8N4E7
	ENSG00000303256	ENST00000793240.1		n.-215G>A		upstream_gene	N/A
	ENSG00000303256	ENST00000793241.1		n.-246G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438412 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715778

African (AFR) AF: 0.00 AC: 0 AN: 31702

American (AMR) AF: 0.00 AC: 0 AN: 43274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.0000521 AC: 2 AN: 38404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106284

Other (OTH) AF: 0.00 AC: 0 AN: 59556

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000224 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.81
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.058
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.015
Sift	Benign	0.047	D
Sift4G	Benign	0.11	T
Polyphen		0.0070	B
Vest4		0.090
MutPred		0.27		Loss of glycosylation at P34 (P = 0.0374)
MVP		0.44
MPC		0.32
ClinPred		0.058	T
GERP RS		1.2
PromoterAI		-0.0014	Neutral
Varity_R		0.028
gMVP		0.50
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1398561223; hg19: chr5-121187759; COSMIC: COSV58420402;