NM_000143.4:c.1237-26_1237-13dupTCTCTCTCTCTCTC

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-26_1237-13dupTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000143.4(FH):​c.1237-26_1237-13dupTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (158 hom., cov: 0)
  • Exomes 𝑓: 0.023 (154 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -8 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1237054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1237-26_1237-13dupTCTCTCTCTCTCTC		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.1237-26_1237-13dupTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4611_4624dupTCTCTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-26_1237-13dupTCTCTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 5796 AN: 133480 Hom.: 158 Cov.: 0

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.00672

Gnomad EAS AF: 0.00608

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0174

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0388

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0230 AC: 30872 AN: 1341288 Hom.: 154 Cov.: 48 AF XY: 0.0223 AC XY: 14863 AN XY: 667814

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

African (AFR) AF: 0.0157 AC: 486 AN: 30994

American (AMR) AF: 0.00732 AC: 302 AN: 41280

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 141 AN: 24376

East Asian (EAS) AF: 0.00218 AC: 82 AN: 37670

South Asian (SAS) AF: 0.00545 AC: 439 AN: 80486

European-Finnish (FIN) AF: 0.0245 AC: 962 AN: 39216

Middle Eastern (MID) AF: 0.00954 AC: 40 AN: 4194

European-Non Finnish (NFE) AF: 0.0265 AC: 27271 AN: 1027422

Other (OTH) AF: 0.0206 AC: 1149 AN: 55650

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0434 AC: 5796 AN: 133570 Hom.: 158 Cov.: 0 AF XY: 0.0408 AC XY: 2600 AN XY: 63702

African (AFR) AF: 0.0285 AC: 993 AN: 34878

American (AMR) AF: 0.0270 AC: 355 AN: 13148

Ashkenazi Jewish (ASJ) AF: 0.00672 AC: 22 AN: 3274

East Asian (EAS) AF: 0.00609 AC: 28 AN: 4598

South Asian (SAS) AF: 0.0123 AC: 50 AN: 4050

European-Finnish (FIN) AF: 0.0475 AC: 334 AN: 7032

Middle Eastern (MID) AF: 0.0185 AC: 5 AN: 270

European-Non Finnish (NFE) AF: 0.0596 AC: 3793 AN: 63660

Other (OTH) AF: 0.0384 AC: 69 AN: 1796

Alfa AF: 0.0266 Hom.: 226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Nov 08, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

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

Hereditary leiomyomatosis and renal cell cancer Benign:1

Jun 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

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;