rs3848519

Variant names:

• chr18-57580104-C-A
• rs3848519
• NM_000140.5:c.163G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-57580104-C-A
• chr18-57580104-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000140.5(FECH):​c.163G>T​(p.Gly55Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,968 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G55S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.020 (55 hom., cov: 32)
  • Exomes 𝑓: 0.022 (453 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: 0.874
• Publications: 17 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, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.002217114).
• BP6: Variant 18-57580104-C-A is Benign according to our data. Variant chr18-57580104-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0203 (3081/152130) while in subpopulation SAS AF = 0.0512 (246/4802). AF 95% confidence interval is 0.046. There are 55 homozygotes in GnomAd4. There are 1532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 AD,AR gene

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.163G>T	p.Gly55Cys	missense	Exon 2 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.163G>T	p.Gly55Cys	missense	Exon 2 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.163G>T	p.Gly55Cys	missense	Exon 2 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.163G>T	p.Gly55Cys	missense	Exon 2 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.163G>T	p.Gly55Cys	missense	Exon 2 of 11	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.163G>T	p.Gly55Cys	missense	Exon 2 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3083 AN: 152012 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0221 AC: 5548 AN: 251472 AF XY: 0.0229

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0172

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0218 AC: 31846 AN: 1461838 Hom.: 453 Cov.: 32 AF XY: 0.0224 AC XY: 16299 AN XY: 727216

African (AFR) AF: 0.0151 AC: 505 AN: 33476

American (AMR) AF: 0.0271 AC: 1210 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26136

East Asian (EAS) AF: 0.0115 AC: 455 AN: 39700

South Asian (SAS) AF: 0.0461 AC: 3976 AN: 86250

European-Finnish (FIN) AF: 0.0178 AC: 951 AN: 53414

Middle Eastern (MID) AF: 0.0191 AC: 110 AN: 5746

European-Non Finnish (NFE) AF: 0.0210 AC: 23326 AN: 1111998

Other (OTH) AF: 0.0199 AC: 1200 AN: 60394

GnomAD4 genome AF: 0.0203 AC: 3081 AN: 152130 Hom.: 55 Cov.: 32 AF XY: 0.0206 AC XY: 1532 AN XY: 74370

African (AFR) AF: 0.0154 AC: 640 AN: 41506

American (AMR) AF: 0.0340 AC: 519 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.0155 AC: 80 AN: 5174

South Asian (SAS) AF: 0.0512 AC: 246 AN: 4802

European-Finnish (FIN) AF: 0.0176 AC: 186 AN: 10568

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1244 AN: 68008

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0190 Hom.: 99

Bravo AF: 0.0204

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.0183 AC: 157

ExAC AF: 0.0222 AC: 2693

EpiCase AF: 0.0194

EpiControl AF: 0.0183

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
1	-	2	Protoporphyria, erythropoietic, 1 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	13
DANN	Benign	0.49
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0022	T
MetaSVM	Uncertain	-0.0087	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.87
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.56	N
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Sift4G	Uncertain	0.041	D
Polyphen		0.21	B
Vest4		0.15
MPC		0.72
ClinPred		0.0056	T
GERP RS		1.6
Varity_R		0.088
Mutation Taster		=98/2	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: rs3848519; hg19: chr18-55247336; COSMIC: COSV50490775;