1-241500598-T-TGAGA

Variant names:

• chr1-241500598-T-TGAGA
• rs1553340717
• NM_000143.4:c.1237-9_1237-8insTCTC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000143.4(FH):​c.1237-9_1237-8insTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 58,090 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 0.000052 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0410
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Ambry Genetics
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-241500598-T-TGAGA is Benign according to our data. Variant chr1-241500598-T-TGAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 701907.

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.1237-9_1237-8insTCTC		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.1237-9_1237-8insTCTC		intron	N/A	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.1234-9_1234-8insTCTC		intron	N/A	ENSP00000628468.1
	FH	ENST00000932939.1		c.1189-9_1189-8insTCTC		intron	N/A	ENSP00000602998.1

Frequencies

GnomAD3 genomes AF: 0.0000516 AC: 3 AN: 58090 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00318

Gnomad AMR AF: 0.000158

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: 0.0000370

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000137 AC: 3 AN: 219664 AF XY: 0.00000838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000934

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1353674 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 675618

African (AFR) AF: 0.00 AC: 0 AN: 31384

American (AMR) AF: 0.00 AC: 0 AN: 43518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.00 AC: 0 AN: 38100

South Asian (SAS) AF: 0.00 AC: 0 AN: 83120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025868

Other (OTH) AF: 0.00 AC: 0 AN: 56016

GnomAD4 genome AF: 0.0000516 AC: 3 AN: 58090 Hom.: 0 Cov.: 30 AF XY: 0.0000712 AC XY: 2 AN XY: 28102

⚠️ 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: 13730

American (AMR) AF: 0.000158 AC: 1 AN: 6312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1700

East Asian (EAS) AF: 0.00 AC: 0 AN: 2682

South Asian (SAS) AF: 0.00 AC: 0 AN: 1772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 144

European-Non Finnish (NFE) AF: 0.0000370 AC: 1 AN: 27042

Other (OTH) AF: 0.00 AC: 0 AN: 848

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00242438), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.041

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553340717; hg19: chr1-241663898;