1-241497927-AT-ATTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1PM4_SupportingPP5BS1_SupportingBS2

The NM_000143.4(FH):c.1431_1433dupAAA(p.Lys477dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N478N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 8 hom. )

Consequence

FH
NM_000143.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:8B:1O:1

Conservation

PhyloP100: 1.41

Publications

24 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000143.4

PM4

Nonframeshift variant in NON repetitive region in NM_000143.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-241497927-A-ATTT is Pathogenic according to our data. Variant chr1-241497927-A-ATTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42095.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (157/152284) while in subpopulation NFE AF = 0.00162 (110/68016). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 8 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.1431_1433dupAAA	p.Lys477dup	disruptive_inframe_insertion	Exon 10 of 10	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FH	ENST00000366560.4	TSL:1 MANE Select	c.1431_1433dupAAA	p.Lys477dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000355518.4	P07954-1
FH	ENST00000958409.1		c.1428_1430dupAAA	p.Lys476dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000628468.1
FH	ENST00000932939.1		c.1383_1385dupAAA	p.Lys461dup	disruptive_inframe_insertion	Exon 10 of 10	ENSP00000602998.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00104

AC:

259

AN:

249492

AF XY:

0.000992

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00201

AC:

2933

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1430

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33470

American (AMR)

AF:

0.000403

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

136

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00235

AC:

2616

AN:

1111948

Other (OTH)

AF:

0.00237

AC:

143

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00103

AC:

157

AN:

152284

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41556

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.00247

Hom.:

Bravo

AF:

0.00111

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00196

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (14)

Fumarase deficiency (7)

Hereditary leiomyomatosis and renal cell cancer (4)

Hereditary cancer-predisposing syndrome (2)

FH-related disorder (1)

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer (1)

Inherited renal cancer (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=55/45

disease causing (ClinVar)

(source)

Splicing

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

Publications

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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