chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-36_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTC

Variant summary

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

The NM_000143.4(FH):​c.1237-36_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTC 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 0.00019 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000013 (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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1237-36_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-36_1237-13dupTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000958409.1		c.1234-36_1234-13dupTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000628468.1
	FH	ENST00000932939.1		c.1189-36_1189-13dupTCTCTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000602998.1

Frequencies

GnomAD3 genomes AF: 0.000194 AC: 26 AN: 133796 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000344

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: 0.000204

Gnomad OTH AF: 0.000562

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000133 AC: 18 AN: 1356812 Hom.: 0 Cov.: 48 AF XY: 0.0000163 AC XY: 11 AN XY: 675466

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

African (AFR) AF: 0.0000959 AC: 3 AN: 31296

American (AMR) AF: 0.00 AC: 0 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24454

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

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

European-Finnish (FIN) AF: 0.0000251 AC: 1 AN: 39766

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

European-Non Finnish (NFE) AF: 0.0000125 AC: 13 AN: 1040868

Other (OTH) AF: 0.0000178 AC: 1 AN: 56294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000423039), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000194 AC: 26 AN: 133886 Hom.: 1 Cov.: 0 AF XY: 0.000188 AC XY: 12 AN XY: 63868

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

African (AFR) AF: 0.000343 AC: 12 AN: 34962

American (AMR) AF: 0.00 AC: 0 AN: 13172

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4600

South Asian (SAS) AF: 0.00 AC: 0 AN: 4054

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

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

European-Non Finnish (NFE) AF: 0.000204 AC: 13 AN: 63790

Other (OTH) AF: 0.000556 AC: 1 AN: 1798

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000652256), 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;