NM_000143.4:c.556-7C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000143.4(FH):​c.556-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FH
NM_000143.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0004739
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.236

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
Variant 1-241508792-G-A is Benign according to our data. Variant chr1-241508792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529829.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHNM_000143.4 linkc.556-7C>T splice_region_variant, intron_variant Intron 4 of 9 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.556-7C>T splice_region_variant, intron_variant Intron 4 of 9 1 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000401
AC:
1
AN:
249386
AF XY:
0.00000741
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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
AF:
6.85e-7
AC:
1
AN:
1459424
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726034
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33364
American (AMR)
AF:
0.00
AC:
0
AN:
44544
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39646
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
85920
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53362
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1110458
Other (OTH)
AF:
0.00
AC:
0
AN:
60296
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
May 11, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.64
CADD
Benign
7.6
DANN
Benign
0.69
PhyloP100
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00047
dbscSNV1_RF
Benign
0.13
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs780483420; hg19: chr1-241672092; COSMIC: COSV63819317; COSMIC: COSV63819317; API