1-241497928-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000143.4(FH):​c.1433A>T​(p.Asn478Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N478S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

FH
NM_000143.4 missense

Scores

5
12
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

Publications

0 publications found
Variant links:
Genes affected
FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]
FH Gene-Disease associations (from GenCC):
  • hereditary leiomyomatosis and renal cell cancer
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
  • fumaric aciduria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • pheochromocytoma-paraganglioma
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • leiomyosarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000143.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 132 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.2708 (below the threshold of 3.09). Trascript score misZ: 2.0634 (below the threshold of 3.09). GenCC associations: The gene is linked to fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma, pheochromocytoma-paraganglioma.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHNM_000143.4 linkc.1433A>T p.Asn478Ile missense_variant Exon 10 of 10 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.1433A>T p.Asn478Ile missense_variant Exon 10 of 10 1 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.83
D
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.51
D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Pathogenic
3.5
H
PhyloP100
1.4
PrimateAI
Benign
0.42
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.48
P
Vest4
0.31
MutPred
0.48
Gain of catalytic residue at N478 (P = 0.0276);
MVP
0.93
MPC
0.72
ClinPred
0.98
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.86
Mutation Taster
=66/34
polymorphism

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

Publications

Other links and lift over

dbSNP: rs201886827; hg19: chr1-241661228; API