rs12968109

Variant names:

• chr18-57576579-G-A
• rs12968109
• NM_000140.5:c.195-3214C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-57576579-G-A
• chr18-57576579-G-C
• chr18-57576579-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000140.5(FECH):​c.195-3214C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 151,970 control chromosomes in the GnomAD database, including 5,475 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 (5475 hom., cov: 32)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.195-3214C>T		intron_variant	Intron 2 of 10	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.195-3214C>T		intron_variant	Intron 2 of 10	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38679 AN: 151852 Hom.: 5462 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.255 AC: 38719 AN: 151970 Hom.: 5475 Cov.: 32 AF XY: 0.246 AC XY: 18256 AN XY: 74284

African (AFR) AF: 0.350 AC: 14493 AN: 41410

American (AMR) AF: 0.182 AC: 2784 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 873 AN: 3472

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5180

South Asian (SAS) AF: 0.0936 AC: 451 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1910 AN: 10550

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.256 AC: 17385 AN: 67942

Other (OTH) AF: 0.246 AC: 521 AN: 2114

Alfa AF: 0.207 Hom.: 841

Bravo AF: 0.259

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.73
PhyloP100		1.0
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: rs12968109; hg19: chr18-55243811;