Genetic Variant ERRFI1:p.Arg245Lys (chr1-8013865-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018948.4(ERRFI1):c.734G>A(p.Arg245Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ERRFI1
NM_018948.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.470

Variant links:

Genes affected

ERRFI1 (HGNC:18185): (ERBB receptor feedback inhibitor 1) ERRFI1 is a cytoplasmic protein whose expression is upregulated with cell growth (Wick et al., 1995 [PubMed 7641805]). It shares significant homology with the protein product of rat gene-33, which is induced during cell stress and mediates cell signaling (Makkinje et al., 2000 [PubMed 10749885]; Fiorentino et al., 2000 [PubMed 11003669]).[supplied by OMIM, Mar 2008]

ERRFI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014195502).

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERRFI1	NM_018948.4 link	c.734G>A	p.Arg245Lys	missense_variant	Exon 4 of 4	ENST00000377482.10	NP_061821.1	Q9UJM3I6S2Y9B3KTV8
ERRFI1	XM_047422698.1 link	c.734G>A	p.Arg245Lys	missense_variant	Exon 3 of 3		XP_047278654.1
ERRFI1	XM_005263477.4 link	c.581G>A	p.Arg194Lys	missense_variant	Exon 3 of 3		XP_005263534.1
ERRFI1	XM_047422701.1 link	c.509G>A	p.Arg170Lys	missense_variant	Exon 2 of 2		XP_047278657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERRFI1	ENST00000377482.10 link	c.734G>A	p.Arg245Lys	missense_variant	Exon 4 of 4	1	NM_018948.4	ENSP00000366702.5		Q9UJM3

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

251296

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000164

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.734G>A (p.R245K) alteration is located in exon 4 (coding exon 3) of the ERRFI1 gene. This alteration results from a G to A substitution at nucleotide position 734, causing the arginine (R) at amino acid position 245 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.17

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.65

M_CAP

Benign

0.0082

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.27

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.030

REVEL

Benign

0.051

Sift

Benign

0.97

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.11

MVP

0.24

MPC

0.18

ClinPred

0.0060

GERP RS

2.2

Varity_R

0.055

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over