rs2269219

Variant names:

• chr18-57580222-G-A
• rs2269219
• NM_000140.5:c.68-23C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-57580222-G-A
• chr18-57580222-G-C
• chr18-57580222-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000140.5(FECH):​c.68-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,044 control chromosomes in the GnomAD database, including 38,415 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 0.27 (6866 hom., cov: 32)
  • Exomes 𝑓: 0.19 (31549 hom.)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: 0.509
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-57580222-G-A is Benign according to our data. Variant chr18-57580222-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 550.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 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.68-23C>T		intron	N/A	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.68-23C>T		intron	N/A	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.68-23C>T		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.68-23C>T		intron	N/A	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.68-23C>T		intron	N/A	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.68-23C>T		intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41599 AN: 151926 Hom.: 6851 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.251 AC: 62889 AN: 250832 AF XY: 0.240

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.194 AC: 283768 AN: 1461000 Hom.: 31549 Cov.: 34 AF XY: 0.194 AC XY: 141175 AN XY: 726836

African (AFR) AF: 0.454 AC: 15194 AN: 33452

American (AMR) AF: 0.398 AC: 17798 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5868 AN: 26130

East Asian (EAS) AF: 0.366 AC: 14537 AN: 39694

South Asian (SAS) AF: 0.257 AC: 22140 AN: 86244

European-Finnish (FIN) AF: 0.231 AC: 12327 AN: 53284

Middle Eastern (MID) AF: 0.239 AC: 1376 AN: 5764

European-Non Finnish (NFE) AF: 0.164 AC: 182079 AN: 1111368

Other (OTH) AF: 0.206 AC: 12449 AN: 60376

GnomAD4 genome AF: 0.274 AC: 41673 AN: 152044 Hom.: 6866 Cov.: 32 AF XY: 0.278 AC XY: 20647 AN XY: 74320

African (AFR) AF: 0.447 AC: 18527 AN: 41448

American (AMR) AF: 0.303 AC: 4622 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 744 AN: 3468

East Asian (EAS) AF: 0.324 AC: 1673 AN: 5164

South Asian (SAS) AF: 0.251 AC: 1210 AN: 4816

European-Finnish (FIN) AF: 0.246 AC: 2596 AN: 10568

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11584 AN: 67988

Other (OTH) AF: 0.262 AC: 553 AN: 2108

Alfa AF: 0.205 Hom.: 13583

Bravo AF: 0.288

Asia WGS AF: 0.294 AC: 1020 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	4	Protoporphyria, erythropoietic, 1 (6)
-	-	2	not provided (2)
-	-	1	Jaundice;C0041834:Erythema (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.0
DANN	Benign	0.51
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2269219; hg19: chr18-55247454; COSMIC: COSV50490971;