1-241497736-C-A

Variant names:

• chr1-241497736-C-A
• rs202167168
• NM_000143.4:c.*92G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000143.4(FH):​c.*92G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,168,636 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: FH NM_000143.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: -0.256
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*92G>T		3_prime_UTR	Exon 10 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.*92G>T		3_prime_UTR	Exon 10 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000958406.1		c.*92G>T		3_prime_UTR	Exon 10 of 10	ENSP00000628465.1
	FH	ENST00000865384.1		c.*92G>T		3_prime_UTR	Exon 8 of 8	ENSP00000535443.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 142 AN: 1016366 Hom.: 1 Cov.: 13 AF XY: 0.000130 AC XY: 67 AN XY: 514488

African (AFR) AF: 0.00 AC: 0 AN: 23466

American (AMR) AF: 0.00 AC: 0 AN: 31924

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 92 AN: 22036

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33816

South Asian (SAS) AF: 0.0000300 AC: 2 AN: 66690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3260

European-Non Finnish (NFE) AF: 0.0000321 AC: 24 AN: 747346

Other (OTH) AF: 0.000511 AC: 23 AN: 45016

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152270 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 15 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary leiomyomatosis and renal cell cancer (2)
-	1	-	Fumarase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.24
DANN	Benign	0.52
PhyloP100		-0.26

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: rs202167168; hg19: chr1-241661036;