chr18-57579636-T-C

Variant names:

• chr18-57579636-T-C
• rs8099511
• NM_000140.5:c.194+437A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000140.5(FECH):​c.194+437A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 151,964 control chromosomes in the GnomAD database, including 14,273 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14273 hom., cov: 31)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.194+437A>G		intron_variant	Intron 2 of 10	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.194+437A>G		intron_variant	Intron 2 of 10	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64599 AN: 151846 Hom.: 14251 Cov.: 31

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.422

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.425 AC: 64653 AN: 151964 Hom.: 14273 Cov.: 31 AF XY: 0.419 AC XY: 31095 AN XY: 74276

African (AFR) AF: 0.455 AC: 18849 AN: 41430

American (AMR) AF: 0.384 AC: 5865 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1572 AN: 3472

East Asian (EAS) AF: 0.0337 AC: 175 AN: 5186

South Asian (SAS) AF: 0.321 AC: 1542 AN: 4810

European-Finnish (FIN) AF: 0.404 AC: 4262 AN: 10558

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 31007 AN: 67924

Other (OTH) AF: 0.417 AC: 879 AN: 2110

Alfa AF: 0.446 Hom.: 30428

Bravo AF: 0.422

Asia WGS AF: 0.220 AC: 768 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.84
DANN	Benign	0.39
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs8099511; hg19: chr18-55246868;