chr1-241519719-A-T

Variant names:

• chr1-241519719-A-T
• rs112335468
• NM_000143.4:c.4T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000143.4(FH):​c.4T>A​(p.Tyr2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.216
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24808729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.4T>A	p.Tyr2Asn	missense_variant	Exon 1 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.4T>A	p.Tyr2Asn	missense_variant	Exon 1 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391056 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685234

African (AFR) AF: 0.00 AC: 0 AN: 31102

American (AMR) AF: 0.00 AC: 0 AN: 35402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25030

East Asian (EAS) AF: 0.00 AC: 0 AN: 35452

South Asian (SAS) AF: 0.00 AC: 0 AN: 78580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075226

Other (OTH) AF: 0.00 AC: 0 AN: 57520

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Dec 13, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: Not Available; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with FH-related conditions. This sequence change replaces tyrosine with asparagine at codon 2 of the FH protein (p.Tyr2Asn). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y2N variant (also known as c.4T>A), located in coding exon 1 of the FH gene, results from a T to A substitution at nucleotide position 4. The tyrosine at codon 2 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.22
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.34
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.42
MutPred		0.17		Gain of methylation at R3 (P = 0.0756);
MVP		0.90
MPC		0.46
ClinPred		0.21	T
GERP RS		-1.6
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.63
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs112335468; hg19: chr1-241683019;