chr5-121852550-A-G

Variant names:

• chr5-121852550-A-G
• rs779245431
• NM_177478.2:c.587A>G

Variant summary

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

The NM_177478.2(FTMT):​c.587A>G​(p.Tyr196Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FTMT NM_177478.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.587A>G	p.Tyr196Cys	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.587A>G	p.Tyr196Cys	missense	Exon 1 of 1	ENSP00000313691.1	Q8N4E7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.63	N
PhyloP100		7.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.69	P
Vest4		0.25
MutPred		0.55		Loss of stability (P = 0.1703)
MVP		0.87
MPC		0.36
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.70
gMVP		0.42
Mutation Taster		=64/36	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: rs779245431; hg19: chr5-121188245;