1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-TGAGA-T
• rs144131869
• NM_000143.4:c.1237-16_1237-13delTCTC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_000143.4(FH):​c.1237-16_1237-13delTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,486,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0052 (0 hom.)
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• 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 -5 ACMG points.

• BP6: Variant 1-241500602-TGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296872.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00354 (474/133868) while in subpopulation EAS AF = 0.0104 (48/4598). AF 95% confidence interval is 0.00809. There are 0 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.1237-16_1237-13delTCTC		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.1237-16_1237-13delTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4621_4624delTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-16_1237-13delTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 473 AN: 133780 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00183

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00566

Gnomad FIN AF: 0.000141

Gnomad MID AF: 0.0139

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00393

GnomAD4 exome AF: 0.00518 AC: 7002 AN: 1352738 Hom.: 0 AF XY: 0.00518 AC XY: 3490 AN XY: 673448

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

African (AFR) AF: 0.0209 AC: 651 AN: 31094

American (AMR) AF: 0.0165 AC: 681 AN: 41224

Ashkenazi Jewish (ASJ) AF: 0.00596 AC: 145 AN: 24346

East Asian (EAS) AF: 0.0141 AC: 527 AN: 37378

South Asian (SAS) AF: 0.00725 AC: 584 AN: 80558

European-Finnish (FIN) AF: 0.00402 AC: 159 AN: 39580

Middle Eastern (MID) AF: 0.00815 AC: 34 AN: 4174

European-Non Finnish (NFE) AF: 0.00373 AC: 3868 AN: 1038290

Other (OTH) AF: 0.00629 AC: 353 AN: 56094

⚠️ 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: 0.00354 AC: 474 AN: 133868 Hom.: 0 Cov.: 0 AF XY: 0.00349 AC XY: 223 AN XY: 63850

African (AFR) AF: 0.00595 AC: 208 AN: 34960

American (AMR) AF: 0.00532 AC: 70 AN: 13164

Ashkenazi Jewish (ASJ) AF: 0.00183 AC: 6 AN: 3274

East Asian (EAS) AF: 0.0104 AC: 48 AN: 4598

South Asian (SAS) AF: 0.00567 AC: 23 AN: 4054

European-Finnish (FIN) AF: 0.000141 AC: 1 AN: 7096

Middle Eastern (MID) AF: 0.0148 AC: 4 AN: 270

European-Non Finnish (NFE) AF: 0.00168 AC: 107 AN: 63788

Other (OTH) AF: 0.00389 AC: 7 AN: 1798

Alfa AF: 0.00 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

May 19, 2023

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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

Hereditary cancer-predisposing syndrome Benign:1

Jun 25, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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;