rs118204037

Variant names:

• chr18-57559148-C-T
• rs118204037
• NM_000140.5:c.801G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-57559148-C-T
• chr18-57559148-C-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS1_Supporting

The NM_000140.5(FECH):​c.801G>A​(p.Met267Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,602,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. M267T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 5.45
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000140.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.26054183).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00108 (164/152238) while in subpopulation NFE AF = 0.00172 (117/68026). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.801G>A	p.Met267Ile	missense	Exon 7 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.819G>A	p.Met273Ile	missense	Exon 7 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.801G>A	p.Met267Ile	missense	Exon 7 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.801G>A	p.Met267Ile	missense	Exon 7 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.819G>A	p.Met273Ile	missense	Exon 7 of 11	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.801G>A	p.Met267Ile	missense	Exon 7 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00104 AC: 261 AN: 251240 AF XY: 0.00110

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00126 AC: 1830 AN: 1450392 Hom.: 0 Cov.: 25 AF XY: 0.00125 AC XY: 900 AN XY: 722352

African (AFR) AF: 0.000181 AC: 6 AN: 33118

American (AMR) AF: 0.000783 AC: 35 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86026

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53336

Middle Eastern (MID) AF: 0.00574 AC: 33 AN: 5748

European-Non Finnish (NFE) AF: 0.00143 AC: 1575 AN: 1101814

Other (OTH) AF: 0.00112 AC: 67 AN: 59954

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74458

African (AFR) AF: 0.000193 AC: 8 AN: 41528

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.26	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.84
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.012	D
Polyphen		0.88	P
Vest4		0.79
MutPred		0.81		Loss of disorder (P = 0.0921)
MVP		0.98
MPC		0.94
ClinPred		0.14	T
GERP RS		4.8
PromoterAI		0.0031	Neutral
Varity_R		0.76
Mutation Taster		=18/82	disease causing

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: rs118204037; hg19: chr18-55226380;