NM_000143.4:c.1237-18_1237-13dupTCTCTC

Variant names:

• chr1-241500602-T-TGAGAGA
• rs144131869
• NM_000143.4:c.1237-18_1237-13dupTCTCTC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000143.4(FH):​c.1237-18_1237-13dupTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (2680 hom., cov: 0)
  • Exomes 𝑓: 0.15 (564 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: -0.993
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296867.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1237-18_1237-13dupTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-18_1237-13dupTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4619_4624dupTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-18_1237-13dupTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 26994 AN: 133502 Hom.: 2678 Cov.: 0

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.199

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.152 AC: 202299 AN: 1326574 Hom.: 564 Cov.: 48 AF XY: 0.151 AC XY: 99564 AN XY: 659940

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.142 AC: 4304 AN: 30390

American (AMR) AF: 0.104 AC: 4167 AN: 40172

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2987 AN: 23702

East Asian (EAS) AF: 0.119 AC: 4311 AN: 36344

South Asian (SAS) AF: 0.133 AC: 10469 AN: 78430

European-Finnish (FIN) AF: 0.115 AC: 4467 AN: 38838

Middle Eastern (MID) AF: 0.120 AC: 493 AN: 4104

European-Non Finnish (NFE) AF: 0.160 AC: 162969 AN: 1019678

Other (OTH) AF: 0.148 AC: 8132 AN: 54916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.202 AC: 27016 AN: 133592 Hom.: 2680 Cov.: 0 AF XY: 0.201 AC XY: 12811 AN XY: 63710

African (AFR) AF: 0.175 AC: 6118 AN: 34900

American (AMR) AF: 0.188 AC: 2476 AN: 13140

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 626 AN: 3264

East Asian (EAS) AF: 0.172 AC: 787 AN: 4586

South Asian (SAS) AF: 0.213 AC: 861 AN: 4040

European-Finnish (FIN) AF: 0.174 AC: 1233 AN: 7072

Middle Eastern (MID) AF: 0.189 AC: 51 AN: 270

European-Non Finnish (NFE) AF: 0.226 AC: 14375 AN: 63658

Other (OTH) AF: 0.200 AC: 359 AN: 1798

Alfa AF: 0.143 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Uncertain:2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 09, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Jul 12, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fumarase deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144131869; hg19: chr1-241663902;