rs8339

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	NM_000140.5	MANE Select	c.*248C>T		3_prime_UTR	Exon 11 of 11	NP_000131.2
	FECH	NM_001012515.4		c.*248C>T		3_prime_UTR	Exon 11 of 11	NP_001012533.1
	FECH	NM_001374778.1		c.*248C>T		3_prime_UTR	Exon 10 of 10	NP_001361707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.*248C>T		3_prime_UTR	Exon 11 of 11	ENSP00000262093.6
	FECH	ENST00000652755.1		c.*248C>T		3_prime_UTR	Exon 11 of 11	ENSP00000498358.1
	FECH	ENST00000878110.1		c.*248C>T		3_prime_UTR	Exon 10 of 10	ENSP00000548169.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Protoporphyria, erythropoietic, 1 (1)

Computational scores

Source: dbNSFP v4.9

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;