1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000143.4(FH):​c.1237-16_1237-13dupTCTC 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 0.26 (4472 hom., cov: 0)
  • Exomes 𝑓: 0.24 (433 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 1-241500602-T-TGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296866.

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_1237-13dupTCTC		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_1237-13dupTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4621_4624dupTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-16_1237-13dupTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 34085 AN: 133608 Hom.: 4472 Cov.: 0

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.272

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.239 AC: 315854 AN: 1321580 Hom.: 433 Cov.: 48 AF XY: 0.240 AC XY: 157560 AN XY: 657174

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

African (AFR) AF: 0.145 AC: 4414 AN: 30344

American (AMR) AF: 0.233 AC: 9219 AN: 39602

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5382 AN: 23622

East Asian (EAS) AF: 0.159 AC: 5773 AN: 36324

South Asian (SAS) AF: 0.275 AC: 21324 AN: 77678

European-Finnish (FIN) AF: 0.202 AC: 7843 AN: 38746

Middle Eastern (MID) AF: 0.217 AC: 878 AN: 4044

European-Non Finnish (NFE) AF: 0.245 AC: 248528 AN: 1016462

Other (OTH) AF: 0.228 AC: 12493 AN: 54758

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.255 AC: 34101 AN: 133698 Hom.: 4472 Cov.: 0 AF XY: 0.256 AC XY: 16320 AN XY: 63768

African (AFR) AF: 0.152 AC: 5323 AN: 34924

American (AMR) AF: 0.317 AC: 4162 AN: 13134

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 904 AN: 3272

East Asian (EAS) AF: 0.170 AC: 780 AN: 4596

South Asian (SAS) AF: 0.368 AC: 1491 AN: 4050

European-Finnish (FIN) AF: 0.276 AC: 1957 AN: 7098

Middle Eastern (MID) AF: 0.285 AC: 77 AN: 270

European-Non Finnish (NFE) AF: 0.293 AC: 18671 AN: 63696

Other (OTH) AF: 0.272 AC: 488 AN: 1792

Alfa AF: 0.241 Hom.: 226

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Aug 10, 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 Uncertain:1 Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Expansion of intronic repeat, unlikely to impact splicing. Other expansions near this position (maybe same one? Hard to tell) present in ExAC at moderate frequency (~0.1% E. Asian)

Sep 03, 2021

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Fumarase deficiency Uncertain:1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Dec 16, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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;