chr18-57552997-G-A

Variant names:

• chr18-57552997-G-A
• rs11660001
• NM_000140.5:c.1077+1263C>T

Variant summary

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

The NM_000140.5(FECH):​c.1077+1263C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,068 control chromosomes in the GnomAD database, including 2,773 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 0.18 (2773 hom., cov: 32)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

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.1077+1263C>T		intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.1095+1263C>T		intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.1077+1263C>T		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.1077+1263C>T		intron	N/A	ENSP00000262093.6
	FECH	ENST00000682485.1		n.2515C>T		non_coding_transcript_exon	Exon 9 of 9
	FECH	ENST00000652755.1		c.1095+1263C>T		intron	N/A	ENSP00000498358.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27916 AN: 151950 Hom.: 2771 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.184 AC: 27919 AN: 152068 Hom.: 2773 Cov.: 32 AF XY: 0.183 AC XY: 13591 AN XY: 74342

African (AFR) AF: 0.115 AC: 4781 AN: 41498

American (AMR) AF: 0.150 AC: 2289 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3472

East Asian (EAS) AF: 0.136 AC: 702 AN: 5164

South Asian (SAS) AF: 0.270 AC: 1302 AN: 4814

European-Finnish (FIN) AF: 0.179 AC: 1886 AN: 10564

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15381 AN: 67958

Other (OTH) AF: 0.176 AC: 372 AN: 2116

Alfa AF: 0.208 Hom.: 2708

Bravo AF: 0.177

Asia WGS AF: 0.183 AC: 638 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.49
PhyloP100		0.53
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: rs11660001; hg19: chr18-55220229;