18-57573240-T-G

Variant names:

• chr18-57573240-T-G
• rs786205246
• NM_000140.5:c.314+6A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000140.5(FECH):​c.314+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FECH NM_000140.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002379
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.175
• Publications: 0 publications found

Genes affected

FECH (HGNC:3647): (ferrochelatase) The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.[provided by RefSeq, May 2010]

FECH Gene-Disease associations (from GenCC):

• protoporphyria, erythropoietic, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-57573240-T-G is Pathogenic according to our data. Variant chr18-57573240-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 556.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000140.5. 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
	FECH	NM_000140.5	MANE Select	c.314+6A>C		splice_region intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.332+6A>C		splice_region intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.314+6A>C		splice_region intron	N/A	NP_001361707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.314+6A>C		splice_region intron	N/A	ENSP00000262093.6
	FECH	ENST00000585878.1	TSL:4	n.372A>C		non_coding_transcript_exon	Exon 3 of 3
	FECH	ENST00000592111.1	TSL:2	n.321A>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Protoporphyria, erythropoietic, 1 Pathogenic:1

Jul 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.96
DANN	Benign	0.58
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=79/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.11
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: rs786205246; hg19: chr18-55240472;