Genetic Variant ERBIN:p.Leu189Met (chr5-66021353-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001253697.2(ERBIN):c.565C>A(p.Leu189Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L189L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ERBIN
NM_001253697.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.260

Publications

24 publications found

Variant links:

Genes affected

ERBIN (HGNC:15842): (erbb2 interacting protein) This gene is a member of the leucine-rich repeat and PDZ domain (LAP) family. The encoded protein contains 17 leucine-rich repeats and one PDZ domain. It binds to the unphosphorylated form of the ERBB2 protein and regulates ERBB2 function and localization. It has also been shown to affect the Ras signaling pathway by disrupting Ras-Raf interaction. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ERBIN Gene-Disease associations (from GenCC):

autosomal dominant combined immunodeficiency due to ERBIN deficiency
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ERBIN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253697.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERBIN	NM_001253697.2	MANE Select	c.565C>A	p.Leu189Met	missense	Exon 8 of 26	NP_001240626.1	Q96RT1-1
ERBIN	NM_001253699.2		c.565C>A	p.Leu189Met	missense	Exon 8 of 26	NP_001240628.1	Q96RT1-8
ERBIN	NM_018695.4		c.565C>A	p.Leu189Met	missense	Exon 8 of 25	NP_061165.1	Q96RT1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERBIN	ENST00000284037.10	TSL:1 MANE Select	c.565C>A	p.Leu189Met	missense	Exon 8 of 26	ENSP00000284037.4	Q96RT1-1
ERBIN	ENST00000506030.6	TSL:1	c.565C>A	p.Leu189Met	missense	Exon 8 of 26	ENSP00000426632.1	Q96RT1-8
ERBIN	ENST00000380943.6	TSL:1	c.565C>A	p.Leu189Met	missense	Exon 8 of 25	ENSP00000370330.2	Q96RT1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450950

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

44190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39302

South Asian (SAS)

AF:

0.00

AC:

AN:

85250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5034

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104844

Other (OTH)

AF:

0.0000167

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

-0.23

PhyloP100

0.26

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.43

Sift

Uncertain

0.015

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.82

MutPred

0.73

Loss of stability (P = 0.0592)

MVP

0.34

MPC

0.39

ClinPred

0.92

GERP RS

0.61

Varity_R

0.34

gMVP

0.48

Mutation Taster

=86/14

polymorphism

(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

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