NM_000140.5:c.*248C>T

Variant names:

• chr18-57550464-G-A
• rs8339
• NM_000140.5:c.*248C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000140.5(FECH):​c.*248C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 466,038 control chromosomes in the GnomAD database, including 11,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4835 hom., cov: 32)
  • Exomes 𝑓: 0.17 (6313 hom.)
• Consequence: FECH NM_000140.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.157
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 18-57550464-G-A is Benign according to our data. Variant chr18-57550464-G-A is described in ClinVar as Benign. ClinVar VariationId is 327419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.*248C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.*248C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33238 AN: 151986 Hom.: 4825 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.169 AC: 53073 AN: 313934 Hom.: 6313 Cov.: 4 AF XY: 0.170 AC XY: 28051 AN XY: 164694

African (AFR) AF: 0.379 AC: 3614 AN: 9546

American (AMR) AF: 0.324 AC: 4300 AN: 13264

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 1442 AN: 9576

East Asian (EAS) AF: 0.467 AC: 9006 AN: 19292

South Asian (SAS) AF: 0.215 AC: 8014 AN: 37322

European-Finnish (FIN) AF: 0.110 AC: 1764 AN: 16022

Middle Eastern (MID) AF: 0.173 AC: 232 AN: 1344

European-Non Finnish (NFE) AF: 0.115 AC: 21748 AN: 189460

Other (OTH) AF: 0.163 AC: 2953 AN: 18108

GnomAD4 genome AF: 0.219 AC: 33304 AN: 152104 Hom.: 4835 Cov.: 32 AF XY: 0.221 AC XY: 16426 AN XY: 74362

African (AFR) AF: 0.373 AC: 15458 AN: 41464

American (AMR) AF: 0.290 AC: 4433 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3468

East Asian (EAS) AF: 0.440 AC: 2265 AN: 5150

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4820

European-Finnish (FIN) AF: 0.110 AC: 1160 AN: 10590

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7952 AN: 68004

Other (OTH) AF: 0.224 AC: 473 AN: 2112

Alfa AF: 0.161 Hom.: 5303

Bravo AF: 0.240

Asia WGS AF: 0.339 AC: 1178 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Protoporphyria, erythropoietic, 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.087
DANN	Benign	0.34
PhyloP100		-0.16
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: rs8339; hg19: chr18-55217696;