dbSNP rs17063905: FECH:c.-252A>G (chr18-57586872-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000140.5(FECH):c.-252A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 379,802 control chromosomes in the GnomAD database, including 12,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 7034 hom., cov: 33)

Exomes 𝑓: 0.21 ( 5878 hom. )

Consequence

FECH
NM_000140.5 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.790

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 18-57586872-T-C is Benign according to our data. Variant chr18-57586872-T-C is described in ClinVar as Benign. ClinVar VariationId is 255310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5 link	c.-252A>G		upstream_gene_variant		ENST00000262093.11	NP_000131.2	P22830-1Q7KZA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11 link	c.-252A>G		upstream_gene_variant		1	NM_000140.5	ENSP00000262093.6		P22830-1

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42063

AN:

152038

Hom.:

7017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.0824

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.260

GnomAD4 exome

AF:

0.213

AC:

48535

AN:

227646

Hom.:

5878

AF XY:

0.212

AC XY:

24844

AN XY:

117410

show subpopulations

African (AFR)

AF:

0.442

AC:

2358

AN:

5340

American (AMR)

AF:

0.336

AC:

1822

AN:

5416

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

1649

AN:

7362

East Asian (EAS)

AF:

0.404

AC:

7064

AN:

17476

South Asian (SAS)

AF:

0.245

AC:

2657

AN:

10824

European-Finnish (FIN)

AF:

0.234

AC:

4762

AN:

20342

Middle Eastern (MID)

AF:

0.248

AC:

270

AN:

1090

European-Non Finnish (NFE)

AF:

0.171

AC:

24891

AN:

145426

Other (OTH)

AF:

0.213

AC:

3062

AN:

14370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1695

3390

5084

6779

8474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.277

AC:

42141

AN:

152156

Hom.:

7034

Cov.:

AF XY:

0.280

AC XY:

20847

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.453

AC:

18831

AN:

41524

American (AMR)

AF:

0.302

AC:

4618

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

741

AN:

3470

East Asian (EAS)

AF:

0.330

AC:

1701

AN:

5150

South Asian (SAS)

AF:

0.244

AC:

1177

AN:

4830

European-Finnish (FIN)

AF:

0.251

AC:

2659

AN:

10602

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.172

AC:

11699

AN:

67980

Other (OTH)

AF:

0.262

AC:

555

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1507

3014

4520

6027

7534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.229

Hom.:

612

Bravo

AF:

0.291

Asia WGS

AF:

0.295

AC:

1025

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15850836) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.0

(source)

DANN

Benign

0.60

PhyloP100

-0.79

PromoterAI

0.016

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over