1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-20_1237-13dupTCTCTCTC

Variant summary

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

The NM_000143.4(FH):​c.1237-20_1237-13dupTCTCTCTC 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 0.077 (490 hom., cov: 0)
  • Exomes 𝑓: 0.047 (196 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 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 -9 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296868.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.1237-20_1237-13dupTCTCTCTC		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.1237-20_1237-13dupTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4617_4624dupTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-20_1237-13dupTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 10305 AN: 133414 Hom.: 491 Cov.: 0

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0719

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.0347

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.0626

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0473 AC: 63344 AN: 1338926 Hom.: 196 Cov.: 48 AF XY: 0.0469 AC XY: 31276 AN XY: 666266

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

African (AFR) AF: 0.0945 AC: 2894 AN: 30614

American (AMR) AF: 0.0380 AC: 1554 AN: 40846

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1338 AN: 24044

East Asian (EAS) AF: 0.0627 AC: 2313 AN: 36918

South Asian (SAS) AF: 0.0514 AC: 4063 AN: 79006

European-Finnish (FIN) AF: 0.0399 AC: 1563 AN: 39184

Middle Eastern (MID) AF: 0.0389 AC: 161 AN: 4136

European-Non Finnish (NFE) AF: 0.0453 AC: 46609 AN: 1028720

Other (OTH) AF: 0.0514 AC: 2849 AN: 55458

⚠️ 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: 0.0772 AC: 10309 AN: 133506 Hom.: 490 Cov.: 0 AF XY: 0.0777 AC XY: 4947 AN XY: 63682

African (AFR) AF: 0.128 AC: 4472 AN: 34850

American (AMR) AF: 0.0701 AC: 922 AN: 13150

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 307 AN: 3270

East Asian (EAS) AF: 0.0863 AC: 396 AN: 4588

South Asian (SAS) AF: 0.0564 AC: 228 AN: 4042

European-Finnish (FIN) AF: 0.0590 AC: 418 AN: 7084

Middle Eastern (MID) AF: 0.0296 AC: 8 AN: 270

European-Non Finnish (NFE) AF: 0.0532 AC: 3385 AN: 63596

Other (OTH) AF: 0.0619 AC: 111 AN: 1794

Alfa AF: 0.0454 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jul 30, 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 specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Aug 08, 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

Fumarase deficiency Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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; COSMIC: COSV63817692;