18-57573273-C-T

Position:

• chr18-57573273-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000140.5(FECH):​c.287G>A​(p.Arg96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,052 control chromosomes in the GnomAD database, including 16,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1040 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15231 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.522

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036842525).
• BP6: Variant 18-57573273-C-T is Benign according to our data. Variant chr18-57573273-C-T is described in ClinVar as [Benign]. Clinvar id is 327434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-57573273-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FECH	NM_000140.5	c.287G>A	p.Arg96Gln	missense_variant	3/11	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.287G>A	p.Arg96Gln	missense_variant	3/11	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16084 AN: 152106 Hom.: 1040 Cov.: 33

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0912

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.101 AC: 25374 AN: 251432 Hom.: 1746 AF XY: 0.100 AC XY: 13591 AN XY: 135894

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.0559

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0276

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.136 AC: 198147 AN: 1459828 Hom.: 15231 Cov.: 34 AF XY: 0.133 AC XY: 96522 AN XY: 726364

Gnomad4 AFR exome AF: 0.0526

Gnomad4 AMR exome AF: 0.0603

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.106 AC: 16083 AN: 152224 Hom.: 1040 Cov.: 33 AF XY: 0.0999 AC XY: 7436 AN XY: 74408

Gnomad4 AFR AF: 0.0576

Gnomad4 AMR AF: 0.0910

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0937

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.111

Alfa AF: 0.136 Hom.: 3874

Bravo AF: 0.102

TwinsUK AF: 0.159 AC: 590

ALSPAC AF: 0.153 AC: 590

ESP6500AA AF: 0.0608 AC: 268

ESP6500EA AF: 0.152 AC: 1311

ExAC AF: 0.103 AC: 12496

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.140

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Protoporphyria, erythropoietic, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.95	D;D;D;.;.
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.1	L;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.27	T;T;.;.;.
Sift4G	Benign	0.44	T;T;.;.;T
Polyphen		0.12	B;B;.;.;.
Vest4		0.052
MPC		0.46
ClinPred		0.011	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1041951; hg19: chr18-55240505; COSMIC: COSV50490703;