1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-TGA-T
• rs144131869
• NM_000143.4:c.1237-14_1237-13delTC

Variant summary

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

The NM_000143.4(FH):​c.1237-14_1237-13delTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,479,644 control chromosomes in the GnomAD database, including 99 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (96 hom., cov: 0)
  • Exomes 𝑓: 0.041 (3 hom.)
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 2.18
• 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-TGA-T is Benign according to our data. Variant chr1-241500602-TGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296871.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0697 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.1237-14_1237-13delTC		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.1237-14_1237-13delTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4623_4624delTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-14_1237-13delTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 2928 AN: 133722 Hom.: 96 Cov.: 0

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.00244

Gnomad EAS AF: 0.00629

Gnomad SAS AF: 0.00590

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0408 AC: 54855 AN: 1345834 Hom.: 3 AF XY: 0.0412 AC XY: 27588 AN XY: 669888

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

African (AFR) AF: 0.110 AC: 3407 AN: 30932

American (AMR) AF: 0.0807 AC: 3304 AN: 40948

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 1616 AN: 24182

East Asian (EAS) AF: 0.112 AC: 4167 AN: 37110

South Asian (SAS) AF: 0.0425 AC: 3406 AN: 80076

European-Finnish (FIN) AF: 0.0526 AC: 2067 AN: 39278

Middle Eastern (MID) AF: 0.0602 AC: 251 AN: 4166

European-Non Finnish (NFE) AF: 0.0329 AC: 33981 AN: 1033358

Other (OTH) AF: 0.0476 AC: 2656 AN: 55784

⚠️ 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: 0.0220 AC: 2939 AN: 133810 Hom.: 96 Cov.: 0 AF XY: 0.0219 AC XY: 1396 AN XY: 63822

African (AFR) AF: 0.0720 AC: 2515 AN: 34930

American (AMR) AF: 0.00942 AC: 124 AN: 13164

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 8 AN: 3272

East Asian (EAS) AF: 0.00652 AC: 30 AN: 4600

South Asian (SAS) AF: 0.00543 AC: 22 AN: 4054

European-Finnish (FIN) AF: 0.00311 AC: 22 AN: 7080

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00303 AC: 193 AN: 63778

Other (OTH) AF: 0.0122 AC: 22 AN: 1796

Alfa AF: 0.0524 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

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

Mar 11, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely 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 provided Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Nov 13, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Mar 16, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Fumarase deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FH-related disorder Benign:1

Mar 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=100/0	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: rs144131869; hg19: chr1-241663902;