rs281860678

Variant names:

• chr18-57571588-A-G
• rs2272783
• NM_000140.5:c.315-48T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-57571588-A-G
• chr18-57571588-A-T
• chr18-57571588-A-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000140.5(FECH):​c.315-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 1,613,854 control chromosomes in the GnomAD database, including 8,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.068 (820 hom., cov: 32)
  • Exomes 𝑓: 0.067 (7800 hom.)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:3 O:1
• Conservation: PhyloP100: 0.718
• Publications: 66 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP5: Variant 18-57571588-A-G is Pathogenic according to our data. Variant chr18-57571588-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.324 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.315-48T>C		intron	N/A	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.333-48T>C		intron	N/A	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.315-48T>C		intron	N/A	NP_001361707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.315-48T>C		intron	N/A	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.333-48T>C		intron	N/A	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.315-48T>C		intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10341 AN: 152102 Hom.: 817 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0643

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0969

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0760

GnomAD2 exomes AF: 0.118 AC: 29555 AN: 250318 AF XY: 0.107

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.0625

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.0916

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0878

GnomAD4 exome AF: 0.0670 AC: 97983 AN: 1461634 Hom.: 7800 Cov.: 32 AF XY: 0.0664 AC XY: 48279 AN XY: 727128

African (AFR) AF: 0.0157 AC: 525 AN: 33478

American (AMR) AF: 0.323 AC: 14437 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 1691 AN: 26134

East Asian (EAS) AF: 0.386 AC: 15339 AN: 39694

South Asian (SAS) AF: 0.0887 AC: 7651 AN: 86244

European-Finnish (FIN) AF: 0.0905 AC: 4828 AN: 53344

Middle Eastern (MID) AF: 0.0519 AC: 299 AN: 5764

European-Non Finnish (NFE) AF: 0.0443 AC: 49209 AN: 1111892

Other (OTH) AF: 0.0663 AC: 4004 AN: 60372

GnomAD4 genome AF: 0.0680 AC: 10351 AN: 152220 Hom.: 820 Cov.: 32 AF XY: 0.0744 AC XY: 5534 AN XY: 74406

African (AFR) AF: 0.0190 AC: 790 AN: 41570

American (AMR) AF: 0.183 AC: 2792 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 223 AN: 3468

East Asian (EAS) AF: 0.337 AC: 1740 AN: 5162

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4822

European-Finnish (FIN) AF: 0.0969 AC: 1025 AN: 10582

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0461 AC: 3137 AN: 68000

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0632 Hom.: 1027

Bravo AF: 0.0757

Asia WGS AF: 0.184 AC: 637 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
14	2	-	Protoporphyria, erythropoietic, 1 (17)
5	-	-	not provided (5)
1	-	-	Autosomal erythropoietic protoporphyria (1)
-	1	-	Jaundice;C0041834:Erythema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.36
PhyloP100		0.72
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs2272783; hg19: chr18-55238820; COSMIC: COSV107253510; COSMIC: COSV107253510;