Genetic Variant NM_000140.5:c.464-1197C>A (chr18-57567778-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000140.5(FECH):c.464-1197C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 152,096 control chromosomes in the GnomAD database, including 27,062 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 27059 hom., cov: 33)

Exomes 𝑓: 0.60 ( 3 hom. )

Consequence

FECH
NM_000140.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.60

Publications

4 publications found

Variant links:

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

FECH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.635 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FECH	NM_000140.5	MANE Select	c.464-1197C>A	intron	N/A	NP_000131.2
FECH	NM_001012515.4		c.482-1197C>A	intron	N/A	NP_001012533.1
FECH	NM_001374778.1		c.464-1197C>A	intron	N/A	NP_001361707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FECH	ENST00000262093.11	TSL:1 MANE Select	c.464-1197C>A	intron	N/A	ENSP00000262093.6
FECH	ENST00000652755.1		c.482-1197C>A	intron	N/A	ENSP00000498358.1
FECH	ENST00000878110.1		c.464-1197C>A	intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes

AF:

0.594

AC:

90197

AN:

151958

Hom.:

27042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.517

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.646

Gnomad ASJ

AF:

0.652

Gnomad EAS

AF:

0.618

Gnomad SAS

AF:

0.628

Gnomad FIN

AF:

0.498

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.596

GnomAD4 exome

AF:

0.600

AC:

AN:

Hom.:

AF XY:

0.667

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.594

AC:

90276

AN:

152076

Hom.:

27059

Cov.:

AF XY:

0.590

AC XY:

43893

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.518

AC:

21477

AN:

41480

American (AMR)

AF:

0.645

AC:

9864

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.652

AC:

2263

AN:

3470

East Asian (EAS)

AF:

0.618

AC:

3198

AN:

5174

South Asian (SAS)

AF:

0.628

AC:

3024

AN:

4818

European-Finnish (FIN)

AF:

0.498

AC:

5263

AN:

10558

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.637

AC:

43312

AN:

67972

Other (OTH)

AF:

0.595

AC:

1258

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1907

3815

5722

7630

9537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.607

Hom.:

3482

Bravo

AF:

0.598

Asia WGS

AF:

0.615

AC:

2138

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.021

(source)

DANN

Benign

0.54

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over