Genetic Variant ERFE:p.Phe108Leu (chr2-238162738-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001291832.2(ERFE):c.324C>A(p.Phe108Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,391,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F108F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ERFE
NM_001291832.2 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.50

Publications

0 publications found

Variant links:

Genes affected

ERFE (HGNC:26727): (erythroferrone) Predicted to enable hormone activity. Predicted to be involved in several processes, including negative regulation of gluconeogenesis; positive regulation of glucose import; and positive regulation of insulin receptor signaling pathway. Predicted to act upstream of or within positive regulation of fatty acid transport and regulation of fatty acid metabolic process. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ERFE links:

KLHL30-AS1 (HGNC:31018): (KLHL30 antisense RNA 1)

KLHL30-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291832.2. 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
	ERFE	NM_001291832.2	MANE Select	c.324C>A	p.Phe108Leu	missense splice_region	Exon 3 of 8	NP_001278761.1	Q4G0M1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERFE	ENST00000546354.6	TSL:1 MANE Select	c.324C>A	p.Phe108Leu	missense splice_region	Exon 3 of 8	ENSP00000442304.1	Q4G0M1
ERFE	ENST00000486834.1	TSL:5	n.350C>A		splice_region non_coding_transcript_exon	Exon 3 of 6
KLHL30-AS1	ENST00000845992.1		n.154+7082G>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

146668

AF XY:

0.0000253

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000814

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1391248

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

686630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31484

American (AMR)

AF:

0.0000560

AC:

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25130

East Asian (EAS)

AF:

0.00

AC:

AN:

35706

South Asian (SAS)

AF:

0.00

AC:

AN:

79098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072578

Other (OTH)

AF:

0.00

AC:

AN:

57766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.10

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.00058

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.42

M_CAP

Benign

0.0050

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

PhyloP100

-2.5

PROVEAN

Benign

0.010

REVEL

Benign

0.033

Sift

Benign

0.66

Sift4G

Benign

0.66

Vest4

0.12

MutPred

0.20

Loss of methylation at K107 (P = 0.0264)

MVP

0.10

ClinPred

0.039

GERP RS

-10

Varity_R

0.031

gMVP

0.040

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over