Genetic Variant FH:c.*221_*222delTT (chr1-241497605-TAA-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000143.4(FH):c.*221_*222delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 451,666 control chromosomes in the GnomAD database, including 68 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 56 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

FH
NM_000143.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.58

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 1-241497605-TAA-T is Benign according to our data. Variant chr1-241497605-TAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 296858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.221_222delTT		3_prime_UTR_variant	Exon 10 of 10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560 link	c.221_222delTT		3_prime_UTR_variant	Exon 10 of 10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2350

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00956

GnomAD4 exome

AF:

0.00223

AC:

669

AN:

299346

Hom.:

AF XY:

0.00189

AC XY:

294

AN XY:

155516

show subpopulations

Gnomad4 AFR exome

AF:

0.0507

AC:

502

AN:

9904

Gnomad4 AMR exome

AF:

0.00320

AC:

AN:

11554

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

10194

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

24558

Gnomad4 SAS exome

AF:

0.0000989

AC:

AN:

20214

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

15930

Gnomad4 NFE exome

AF:

0.000203

AC:

AN:

187224

Gnomad4 Remaining exome

AF:

0.00483

AC:

AN:

18422

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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:

0.0155

AC:

2355

AN:

152320

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1130

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0535

AC:

0.0534786

AN:

0.0534786

Gnomad4 AMR

AF:

0.00640

AC:

0.00640272

AN:

0.00640272

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.000414422

AN:

0.000414422

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000176

AC:

0.000176414

AN:

0.000176414

Gnomad4 OTH

AF:

0.00946

AC:

0.00946074

AN:

0.00946074

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0119

Hom.:

Bravo

AF:

0.0177

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fumarase deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over