rs12969847

Positions:

• chr18-57570484-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000140.5(FECH):​c.463+908A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,148 control chromosomes in the GnomAD database, including 4,027 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 0.22 (4027 hom., cov: 32)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.980

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FECH	NM_000140.5	c.463+908A>T		intron_variant		ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.463+908A>T		intron_variant		1	NM_000140.5	ENSP00000262093

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33752 AN: 152030 Hom.: 4019 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0868

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.222 AC: 33785 AN: 152148 Hom.: 4027 Cov.: 32 AF XY: 0.214 AC XY: 15914 AN XY: 74396

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.0867

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.219

Alfa AF: 0.247 Hom.: 588

Bravo AF: 0.221

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.30
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs12969847; hg19: chr18-55237716;