NM_000140.5:c.*4796_*4798delTTA

Variant names:

• chr18-57545913-TTAA-T
• rs137860528
• NM_000140.5:c.*4796_*4798delTTA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000140.5(FECH):​c.*4796_*4798delTTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 152,264 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0012 (4 hom., cov: 32)
• Consequence: FECH NM_000140.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.347
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-57545913-TTAA-T is Benign according to our data. Variant chr18-57545913-TTAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 327331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00116 (176/152264) while in subpopulation EAS AF = 0.0239 (124/5182). AF 95% confidence interval is 0.0205. There are 4 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.*4796_*4798delTTA		3_prime_UTR	Exon 11 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.*4796_*4798delTTA		3_prime_UTR	Exon 11 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.*4796_*4798delTTA		3_prime_UTR	Exon 10 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.*4796_*4798delTTA		3_prime_UTR	Exon 11 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.*4796_*4798delTTA		3_prime_UTR	Exon 11 of 11	ENSP00000498358.1	P22830-2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152146 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152264 Hom.: 4 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74460

African (AFR) AF: 0.0000241 AC: 1 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0239 AC: 124 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.00104

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Protoporphyria, erythropoietic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137860528; hg19: chr18-55213145;