chr18-57573476-T-C

Variant names:

• chr18-57573476-T-C
• rs35655063
• NM_000140.5:c.195-111A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000140.5(FECH):​c.195-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,277,896 control chromosomes in the GnomAD database, including 18,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1735 hom., cov: 32)
  • Exomes 𝑓: 0.16 (16579 hom.)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.535
• Publications: 1 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, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-57573476-T-C is Benign according to our data. Variant chr18-57573476-T-C is described in ClinVar as Benign. ClinVar VariationId is 1243964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	NM_000140.5	MANE Select	c.195-111A>G		intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.213-111A>G		intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.195-111A>G		intron	N/A	NP_001361707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.195-111A>G		intron	N/A	ENSP00000262093.6
	FECH	ENST00000652755.1		c.213-111A>G		intron	N/A	ENSP00000498358.1
	FECH	ENST00000382873.8	TSL:2	c.-22-111A>G		intron	N/A	ENSP00000372326.4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21515 AN: 152100 Hom.: 1736 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.164 AC: 184855 AN: 1125678 Hom.: 16579 AF XY: 0.164 AC XY: 94507 AN XY: 575854

African (AFR) AF: 0.0711 AC: 1911 AN: 26878

American (AMR) AF: 0.145 AC: 6297 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4363 AN: 24048

East Asian (EAS) AF: 0.0102 AC: 387 AN: 38058

South Asian (SAS) AF: 0.146 AC: 11470 AN: 78598

European-Finnish (FIN) AF: 0.192 AC: 7957 AN: 41528

Middle Eastern (MID) AF: 0.134 AC: 628 AN: 4694

European-Non Finnish (NFE) AF: 0.176 AC: 144131 AN: 818958

Other (OTH) AF: 0.156 AC: 7711 AN: 49352

GnomAD4 genome AF: 0.141 AC: 21515 AN: 152218 Hom.: 1735 Cov.: 32 AF XY: 0.142 AC XY: 10604 AN XY: 74434

African (AFR) AF: 0.0749 AC: 3113 AN: 41540

American (AMR) AF: 0.162 AC: 2479 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 656 AN: 3470

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5188

South Asian (SAS) AF: 0.142 AC: 685 AN: 4820

European-Finnish (FIN) AF: 0.197 AC: 2088 AN: 10592

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12038 AN: 67996

Other (OTH) AF: 0.139 AC: 294 AN: 2116

Alfa AF: 0.155 Hom.: 3201

Bravo AF: 0.134

Asia WGS AF: 0.0810 AC: 284 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.79
DANN	Benign	0.69
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35655063; hg19: chr18-55240708;