1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000143.4(FH):​c.1237-22_1237-13delTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,490,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-241500602-TGAGAGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGAGAGA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2575507.Status of the report is criteria_provided_single_submitter, 1 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.1237-22_1237-13delTCTCTCTCTC		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_1237-13delTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4615_4624delTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-22_1237-13delTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0000747 AC: 10 AN: 133802 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000217

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000784

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000929 AC: 126 AN: 1356806 Hom.: 0 AF XY: 0.0000755 AC XY: 51 AN XY: 675462

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

African (AFR) AF: 0.000767 AC: 24 AN: 31294

American (AMR) AF: 0.000265 AC: 11 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24456

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37712

South Asian (SAS) AF: 0.000111 AC: 9 AN: 80768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39770

Middle Eastern (MID) AF: 0.000238 AC: 1 AN: 4204

European-Non Finnish (NFE) AF: 0.0000682 AC: 71 AN: 1040862

Other (OTH) AF: 0.000142 AC: 8 AN: 56294

⚠️ 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: 0.0000747 AC: 10 AN: 133892 Hom.: 0 Cov.: 0 AF XY: 0.000125 AC XY: 8 AN XY: 63870

African (AFR) AF: 0.0000286 AC: 1 AN: 34964

American (AMR) AF: 0.0000759 AC: 1 AN: 13172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.000217 AC: 1 AN: 4600

South Asian (SAS) AF: 0.000247 AC: 1 AN: 4054

European-Finnish (FIN) AF: 0.000141 AC: 1 AN: 7100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000784 AC: 5 AN: 63794

Other (OTH) AF: 0.00 AC: 0 AN: 1798

Alfa AF: 0.00 Hom.: 226

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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		2.2

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;