1-241519721-A-T

Variant names:

• chr1-241519721-A-T
• rs201261794
• NM_000143.4:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_000143.4(FH):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000287 in 1,391,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FH NM_000143.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.81
• Publications: 6 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 30 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 241519593. Lost 0.085 part of the original CDS.
• PS1: Another start lost variant in NM_000143.4 (FH) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241519721-A-T is Pathogenic according to our data. Variant chr1-241519721-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1067423.

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.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000628468.1
	FH	ENST00000932939.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000602998.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1391322 Hom.: 0 Cov.: 31 AF XY: 0.00000584 AC XY: 4 AN XY: 685408

African (AFR) AF: 0.00 AC: 0 AN: 31108

American (AMR) AF: 0.00 AC: 0 AN: 35396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25018

East Asian (EAS) AF: 0.00 AC: 0 AN: 35454

South Asian (SAS) AF: 0.00 AC: 0 AN: 78584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4282

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075466

Other (OTH) AF: 0.00 AC: 0 AN: 57524

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.8
PROVEAN	Benign	-0.43	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.72	P
Vest4		0.93
MutPred		0.61		Loss of stability (P = 0.0139)
MVP		0.98
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.057	Neutral
Varity_R		0.88
gMVP		0.84
Mutation Taster		=35/165	disease causing

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: rs201261794; hg19: chr1-241683021;