rs201887750

Variant names:

• chr1-241519670-G-A
• rs201887750
• NM_000143.4:c.53C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-241519670-G-A
• chr1-241519670-G-C
• chr1-241519670-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000366560.4(FH):​c.53C>T​(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,547,802 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: FH ENST00000366560.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 1.18
• Publications: 2 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: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 132 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.2708 (below the threshold of 3.09). Trascript score misZ: 2.0634 (below the threshold of 3.09). GenCC associations: The gene is linked to fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma, pheochromocytoma-paraganglioma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005271375).
• BP6: Variant 1-241519670-G-A is Benign according to our data. Variant chr1-241519670-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00556 (847/152368) while in subpopulation AFR AF = 0.0194 (807/41586). AF 95% confidence interval is 0.0183. There are 9 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.53C>T	p.Pro18Leu	missense	Exon 1 of 10	NP_000134.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.53C>T	p.Pro18Leu	missense	Exon 1 of 10	ENSP00000355518.4
	FH	ENST00000683521.1		c.53C>T	p.Pro18Leu	missense	Exon 1 of 9	ENSP00000506864.1
	FH	ENST00000493477.2	TSL:3	n.25C>T		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152250 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000441

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00149 AC: 217 AN: 146004 AF XY: 0.00120

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000749

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000550 AC: 767 AN: 1395434 Hom.: 7 Cov.: 31 AF XY: 0.000448 AC XY: 308 AN XY: 688114

African (AFR) AF: 0.0202 AC: 634 AN: 31462

American (AMR) AF: 0.00135 AC: 48 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35694

South Asian (SAS) AF: 0.00 AC: 0 AN: 79022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48320

Middle Eastern (MID) AF: 0.000488 AC: 2 AN: 4100

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078312

Other (OTH) AF: 0.00130 AC: 75 AN: 57756

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152368 Hom.: 9 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74512

African (AFR) AF: 0.0194 AC: 807 AN: 41586

American (AMR) AF: 0.00170 AC: 26 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00257 Hom.: 1

Bravo AF: 0.00665

ESP6500AA AF: 0.0123 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 51

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary leiomyomatosis and renal cell cancer (4)
-	-	4	not specified (5)
-	-	2	Fumarase deficiency (2)
-	-	2	Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer (2)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0053	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.39
Sift	Benign	0.030	D
Sift4G	Uncertain	0.049	D
Polyphen		0.0	B
Vest4		0.23
MVP		0.88
MPC		0.29
ClinPred		0.012	T
GERP RS		4.1
PromoterAI		0.0062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.55
Mutation Taster		=99/1	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: rs201887750; hg19: chr1-241682970; COSMIC: COSV63818953; COSMIC: COSV63818953;