chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-40_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000143.4(FH):​c.1237-40_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1237-40_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC		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.1237-40_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4597_4624dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-40_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.0000149 AC: 2 AN: 133802 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000313

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000221 AC: 3 AN: 1356818 Hom.: 0 Cov.: 48 AF XY: 0.00000296 AC XY: 2 AN XY: 675468

African (AFR) AF: 0.00 AC: 0 AN: 31294

American (AMR) AF: 0.00 AC: 0 AN: 41448

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24456

East Asian (EAS) AF: 0.00 AC: 0 AN: 37714

South Asian (SAS) AF: 0.00 AC: 0 AN: 80770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4204

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1040868

Other (OTH) AF: 0.00 AC: 0 AN: 56296

GnomAD4 genome AF: 0.0000149 AC: 2 AN: 133802 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63768

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

African (AFR) AF: 0.00 AC: 0 AN: 34860

American (AMR) AF: 0.00 AC: 0 AN: 13156

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4610

South Asian (SAS) AF: 0.00 AC: 0 AN: 4066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000313 AC: 2 AN: 63802

Other (OTH) AF: 0.00 AC: 0 AN: 1780

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99

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;