NM_000140.5:c.194+725T>C

Variant names:

• chr18-57579348-A-G
• rs8095390
• NM_000140.5:c.194+725T>C

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+725T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 150,590 control chromosomes in the GnomAD database, including 7,250 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 0.30 (7250 hom., cov: 28)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.664
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.194+725T>C		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+725T>C		intron_variant	Intron 2 of 10	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45557 AN: 150474 Hom.: 7240 Cov.: 28

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.288

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

GnomAD4 genome AF: 0.303 AC: 45601 AN: 150590 Hom.: 7250 Cov.: 28 AF XY: 0.295 AC XY: 21696 AN XY: 73452

African (AFR) AF: 0.331 AC: 13492 AN: 40818

American (AMR) AF: 0.271 AC: 4103 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3462

East Asian (EAS) AF: 0.0130 AC: 67 AN: 5168

South Asian (SAS) AF: 0.160 AC: 766 AN: 4784

European-Finnish (FIN) AF: 0.286 AC: 2932 AN: 10250

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.331 AC: 22416 AN: 67692

Other (OTH) AF: 0.284 AC: 593 AN: 2088

Alfa AF: 0.315 Hom.: 1613

Bravo AF: 0.303

Asia WGS AF: 0.119 AC: 414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.67
PhyloP100		0.66
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: rs8095390; hg19: chr18-55246580;