1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-22_1237-13dupTCTCTCTCTC

Variant summary

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

The NM_000143.4(FH):​c.1237-22_1237-13dupTCTCTCTCTC 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 0.040 (148 hom., cov: 0)
  • Exomes 𝑓: 0.029 (165 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 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-TGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296869.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0562 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.1237-22_1237-13dupTCTCTCTCTC		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.1237-22_1237-13dupTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4615_4624dupTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-22_1237-13dupTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 5350 AN: 133524 Hom.: 146 Cov.: 0

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0372

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0286 AC: 38329 AN: 1341810 Hom.: 165 Cov.: 48 AF XY: 0.0286 AC XY: 19076 AN XY: 667912

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

African (AFR) AF: 0.0419 AC: 1293 AN: 30828

American (AMR) AF: 0.0147 AC: 603 AN: 41146

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 343 AN: 24302

East Asian (EAS) AF: 0.0177 AC: 659 AN: 37264

South Asian (SAS) AF: 0.0380 AC: 3022 AN: 79422

European-Finnish (FIN) AF: 0.0212 AC: 833 AN: 39382

Middle Eastern (MID) AF: 0.0292 AC: 121 AN: 4142

European-Non Finnish (NFE) AF: 0.0290 AC: 29822 AN: 1029746

Other (OTH) AF: 0.0294 AC: 1633 AN: 55578

⚠️ 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: 0.0401 AC: 5356 AN: 133612 Hom.: 148 Cov.: 0 AF XY: 0.0405 AC XY: 2584 AN XY: 63738

African (AFR) AF: 0.0574 AC: 2002 AN: 34884

American (AMR) AF: 0.0294 AC: 387 AN: 13152

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 59 AN: 3270

East Asian (EAS) AF: 0.0348 AC: 160 AN: 4596

South Asian (SAS) AF: 0.0625 AC: 253 AN: 4046

European-Finnish (FIN) AF: 0.0339 AC: 240 AN: 7082

Middle Eastern (MID) AF: 0.0485 AC: 13 AN: 268

European-Non Finnish (NFE) AF: 0.0342 AC: 2175 AN: 63654

Other (OTH) AF: 0.0373 AC: 67 AN: 1794

Alfa AF: 0.00983 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 04, 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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

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

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;