Genetic Variant FH:c.1237-22_1237-13delTCTCTCTCTC (chr1-241500602-TGAGAGAGAGA-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_000143.4(FH):c.1237-22_1237-13delTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,490,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000075 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

FH
NM_000143.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.18

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 1-241500602-TGAGAGAGAGA-T is Benign according to our data. Variant chr1-241500602-TGAGAGAGAGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 2575507.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000929 (126/1356806) while in subpopulation AFR AF = 0.000767 (24/31294). AF 95% confidence interval is 0.000528. There are 0 homozygotes in GnomAdExome4. There are 51 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.1237-22_1237-13delTCTCTCTCTC		intron_variant	Intron 8 of 9	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.1237-22_1237-13delTCTCTCTCTC		intron_variant	Intron 8 of 9	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.0000747

AC:

AN:

133802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000760

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000217

Gnomad SAS

AF:

0.000246

Gnomad FIN

AF:

0.000141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000784

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000929

AC:

126

AN:

1356806

Hom.:

AF XY:

0.0000755

AC XY:

AN XY:

675462

show subpopulations

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

African (AFR)

AF:

0.000767

AC:

AN:

31294

American (AMR)

AF:

0.000265

AC:

AN:

41446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24456

East Asian (EAS)

AF:

0.0000530

AC:

AN:

37712

South Asian (SAS)

AF:

0.000111

AC:

AN:

80768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39770

Middle Eastern (MID)

AF:

0.000238

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.0000682

AC:

AN:

1040862

Other (OTH)

AF:

0.000142

AC:

AN:

56294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000747

AC:

AN:

133892

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

63870

show subpopulations

African (AFR)

AF:

0.0000286

AC:

AN:

34964

American (AMR)

AF:

0.0000759

AC:

AN:

13172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3274

East Asian (EAS)

AF:

0.000217

AC:

AN:

4600

South Asian (SAS)

AF:

0.000247

AC:

AN:

4054

European-Finnish (FIN)

AF:

0.000141

AC:

AN:

7100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000784

AC:

AN:

63794

Other (OTH)

AF:

0.00

AC:

AN:

1798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

226

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar for variant 1:241500602 TGAGAGAGAGA>T . It may be empty.

1-241500602-TGAGAGAGAGA-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over