rs376260223

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000143.4(FH):c.1237-7C>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 0.0000321 in 1,586,462 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

FH
NM_000143.4 splice_region, intron

Scores

Splicing: ADA: 0.00003106

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.345

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: 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

FH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-241500597-G-A is Benign according to our data. Variant chr1-241500597-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418591.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000197 (25/126810) while in subpopulation AFR AF = 0.000708 (24/33890). AF 95% confidence interval is 0.000488. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

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.1237-7C>T		splice_region intron	N/A	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-7C>T	splice_region intron	N/A	ENSP00000355518.4	P07954-1
FH	ENST00000958409.1		c.1234-7C>T	splice_region intron	N/A	ENSP00000628468.1
FH	ENST00000932939.1		c.1189-7C>T	splice_region intron	N/A	ENSP00000602998.1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

126678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000711

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000850

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

247132

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.000501

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:

0.0000178

AC:

AN:

1459652

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726212

show subpopulations

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

African (AFR)

AF:

0.000568

AC:

AN:

33436

American (AMR)

AF:

0.0000447

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111770

Other (OTH)

AF:

0.0000829

AC:

AN:

60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000325627), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

126810

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

AN XY:

61400

show subpopulations

African (AFR)

AF:

0.000708

AC:

AN:

33890

American (AMR)

AF:

0.0000848

AC:

AN:

11786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3120

East Asian (EAS)

AF:

0.00

AC:

AN:

4420

South Asian (SAS)

AF:

0.00

AC:

AN:

3426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59052

Other (OTH)

AF:

0.00

AC:

AN:

1662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000337

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

FH-related disorder (1)

Hereditary cancer-predisposing syndrome (1)

Hereditary leiomyomatosis and renal cell cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.92

(source)

DANN

Benign

0.64

PhyloP100

-0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0040

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over