rs1553342167

Variant names:

• chr1-241519718-T-C
• rs1553342167
• NM_000143.4:c.5A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-241519718-T-C
• chr1-241519718-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_000143.4(FH):​c.5A>G​(p.Tyr2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000259 in 1,543,166 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.24
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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, pheochromocytoma-paraganglioma, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31789798).
• BP6: Variant 1-241519718-T-C is Benign according to our data. Variant chr1-241519718-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529803.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000143.4. 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
	FH	NM_000143.4	MANE Select	c.5A>G	p.Tyr2Cys	missense	Exon 1 of 10	NP_000134.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.5A>G	p.Tyr2Cys	missense	Exon 1 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.5A>G	p.Tyr2Cys	missense	Exon 1 of 10	ENSP00000628468.1
	FH	ENST00000932939.1		c.5A>G	p.Tyr2Cys	missense	Exon 1 of 10	ENSP00000602998.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1391002 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 2 AN XY: 685196

African (AFR) AF: 0.00 AC: 0 AN: 31090

American (AMR) AF: 0.00 AC: 0 AN: 35400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25028

East Asian (EAS) AF: 0.00 AC: 0 AN: 35464

South Asian (SAS) AF: 0.00 AC: 0 AN: 78578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4260

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1075210

Other (OTH) AF: 0.00 AC: 0 AN: 57508

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

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

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Fumarase deficiency (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.32	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.48
Sift	Benign	0.16	T
Sift4G	Benign	0.21	T
Polyphen		0.070	B
Vest4		0.55
MutPred		0.25		Gain of loop (P = 0.1081)
MVP		0.89
MPC		0.35
ClinPred		0.13	T
GERP RS		-0.035
PromoterAI		-0.37	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.65
Mutation Taster		=95/5	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: rs1553342167; hg19: chr1-241683018;