chr18-57552103-C-T

Variant names:

• chr18-57552103-C-T
• rs549777
• NM_000140.5:c.1078-729G>A

Variant summary

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

The NM_000140.5(FECH):​c.1078-729G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 151,532 control chromosomes in the GnomAD database, including 5,314 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 0.25 (5314 hom., cov: 30)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.350
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.1078-729G>A		intron_variant	Intron 9 of 10	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.1078-729G>A		intron_variant	Intron 9 of 10	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37479 AN: 151416 Hom.: 5306 Cov.: 30

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.248 AC: 37517 AN: 151532 Hom.: 5314 Cov.: 30 AF XY: 0.245 AC XY: 18143 AN XY: 74038

African (AFR) AF: 0.395 AC: 16298 AN: 41286

American (AMR) AF: 0.167 AC: 2539 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 586 AN: 3464

East Asian (EAS) AF: 0.144 AC: 738 AN: 5136

South Asian (SAS) AF: 0.207 AC: 993 AN: 4798

European-Finnish (FIN) AF: 0.168 AC: 1752 AN: 10448

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.203 AC: 13791 AN: 67874

Other (OTH) AF: 0.232 AC: 486 AN: 2098

Alfa AF: 0.221 Hom.: 529

Bravo AF: 0.252

Asia WGS AF: 0.182 AC: 634 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.46
PhyloP100		-0.35
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: rs549777; hg19: chr18-55219335; COSMIC: COSV50493002; COSMIC: COSV50493002;