chr1-241500602-T-TGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-28_1237-13dupTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000143.4(FH):​c.1237-28_1237-13dupTCTCTCTCTCTCTCTC 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 0.0088 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0033 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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 -16 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1692238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00884 (1183/133790) while in subpopulation AFR AF = 0.0175 (610/34908). AF 95% confidence interval is 0.0163. There are 12 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

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.1237-28_1237-13dupTCTCTCTCTCTCTCTC		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.1237-28_1237-13dupTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4609_4624dupTCTCTCTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-28_1237-13dupTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1184 AN: 133700 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00130

Gnomad SAS AF: 0.000984

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00507

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00329 AC: 4449 AN: 1353852 Hom.: 11 Cov.: 48 AF XY: 0.00327 AC XY: 2207 AN XY: 673992

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

African (AFR) AF: 0.00796 AC: 248 AN: 31166

American (AMR) AF: 0.00152 AC: 63 AN: 41390

Ashkenazi Jewish (ASJ) AF: 0.00620 AC: 151 AN: 24350

East Asian (EAS) AF: 0.000345 AC: 13 AN: 37692

South Asian (SAS) AF: 0.00105 AC: 85 AN: 80696

European-Finnish (FIN) AF: 0.00368 AC: 146 AN: 39630

Middle Eastern (MID) AF: 0.00262 AC: 11 AN: 4194

European-Non Finnish (NFE) AF: 0.00340 AC: 3526 AN: 1038570

Other (OTH) AF: 0.00367 AC: 206 AN: 56164

⚠️ 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: 0.00884 AC: 1183 AN: 133790 Hom.: 12 Cov.: 0 AF XY: 0.00838 AC XY: 535 AN XY: 63812

African (AFR) AF: 0.0175 AC: 610 AN: 34908

American (AMR) AF: 0.00433 AC: 57 AN: 13170

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 33 AN: 3272

East Asian (EAS) AF: 0.00130 AC: 6 AN: 4598

South Asian (SAS) AF: 0.000987 AC: 4 AN: 4054

European-Finnish (FIN) AF: 0.00183 AC: 13 AN: 7094

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

European-Non Finnish (NFE) AF: 0.00707 AC: 451 AN: 63766

Other (OTH) AF: 0.00502 AC: 9 AN: 1794

Alfa AF: 0.00 Hom.: 226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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

Hereditary leiomyomatosis and renal cell cancer Benign:1

Sep 08, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer Benign:1

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Mar 01, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

FH-related disorder Benign:1

Aug 04, 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		-0.99
Mutation Taster		=100/0	polymorphism

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;