1-241497605-TAA-T

Variant names:

• chr1-241497605-TAA-T
• rs112946286
• NM_000143.4:c.*221_*222delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.58
• Publications: 1 publications found

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

ACMG classification

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 Benign/Likely_benign. ClinVar VariationId 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.

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.*221_*222delTT		3_prime_UTR	Exon 10 of 10	NP_000134.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.*221_*222delTT		3_prime_UTR	Exon 10 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000493477.2	TSL:3	n.2257_2258delTT		non_coding_transcript_exon	Exon 10 of 10
	FH	ENST00000682162.1		n.*1597_*1598delTT		non_coding_transcript_exon	Exon 11 of 11	ENSP00000508203.1	A0A804HL52

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2350 AN: 152202 Hom.: 55 Cov.: 31

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.: 12 AF XY: 0.00189 AC XY: 294 AN XY: 155516

African (AFR) AF: 0.0507 AC: 502 AN: 9904

American (AMR) AF: 0.00320 AC: 37 AN: 11554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10194

East Asian (EAS) AF: 0.00 AC: 0 AN: 24558

South Asian (SAS) AF: 0.0000989 AC: 2 AN: 20214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15930

Middle Eastern (MID) AF: 0.000743 AC: 1 AN: 1346

European-Non Finnish (NFE) AF: 0.000203 AC: 38 AN: 187224

Other (OTH) AF: 0.00483 AC: 89 AN: 18422

GnomAD4 genome AF: 0.0155 AC: 2355 AN: 152320 Hom.: 56 Cov.: 31 AF XY: 0.0152 AC XY: 1130 AN XY: 74482

African (AFR) AF: 0.0535 AC: 2223 AN: 41568

American (AMR) AF: 0.00640 AC: 98 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68022

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0119 Hom.: 5

Bravo AF: 0.0177

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary leiomyomatosis and renal cell cancer (2)
-	-	1	Fumarase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
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

Other links and lift over

dbSNP: rs112946286; hg19: chr1-241660905;