NM_000143.4:c.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000143.4(FH):​c.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGAGAGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1692240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00177 (237/133868) while in subpopulation AFR AF = 0.00383 (134/34954). AF 95% confidence interval is 0.00331. There are 3 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC		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.1237-32_1237-13dupTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.1234-32_1234-13dupTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000628468.1
	FH	ENST00000932939.1		c.1189-32_1189-13dupTCTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000602998.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 237 AN: 133778 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000228

Gnomad ASJ AF: 0.00153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000398 AC: 540 AN: 1356380 Hom.: 0 Cov.: 48 AF XY: 0.000379 AC XY: 256 AN XY: 675240

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

African (AFR) AF: 0.00112 AC: 35 AN: 31274

American (AMR) AF: 0.000193 AC: 8 AN: 41438

Ashkenazi Jewish (ASJ) AF: 0.000982 AC: 24 AN: 24438

East Asian (EAS) AF: 0.00 AC: 0 AN: 37710

South Asian (SAS) AF: 0.000161 AC: 13 AN: 80752

European-Finnish (FIN) AF: 0.000226 AC: 9 AN: 39758

Middle Eastern (MID) AF: 0.000238 AC: 1 AN: 4202

European-Non Finnish (NFE) AF: 0.000405 AC: 421 AN: 1040538

Other (OTH) AF: 0.000515 AC: 29 AN: 56270

⚠️ 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: 0.00177 AC: 237 AN: 133868 Hom.: 3 Cov.: 0 AF XY: 0.00169 AC XY: 108 AN XY: 63858

African (AFR) AF: 0.00383 AC: 134 AN: 34954

American (AMR) AF: 0.000228 AC: 3 AN: 13170

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 5 AN: 3274

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

South Asian (SAS) AF: 0.000247 AC: 1 AN: 4054

European-Finnish (FIN) AF: 0.000282 AC: 2 AN: 7100

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00141 AC: 90 AN: 63782

Other (OTH) AF: 0.00 AC: 0 AN: 1798

Alfa AF: 0.00 Hom.: 226

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary leiomyomatosis and renal cell cancer (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism

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;