rs35655063

Positions:

• chr18-57573476-T-C

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.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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FECH	NM_000140.5	c.195-111A>G		intron_variant		ENST00000262093.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FECH	ENST00000262093.11	c.195-111A>G		intron_variant		1	NM_000140.5

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

Gnomad4 AFR exome AF: 0.0711

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.0102

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.156

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

Gnomad4 AFR AF: 0.0749

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.139

Alfa AF: 0.151 Hom.: 239

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.79
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs35655063; hg19: chr18-55240708;