5-65992849-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001253697.2(ERBIN):c.131T>C(p.Phe44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBIN NM_001253697.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBIN	NM_001253697.2	c.131T>C	p.Phe44Ser	missense_variant	3/26	ENST00000284037.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBIN	ENST00000284037.10	c.131T>C	p.Phe44Ser	missense_variant	3/26	1	NM_001253697.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 44 of the ERBIN protein (p.Phe44Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ERBIN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T;.;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.015	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;T;D;D;D;D;D
Polyphen		0.98	D;D;B;P;D;.;.;P
Vest4		0.62
MutPred		0.59		Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);
MVP		0.17
MPC		0.53
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.67
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-65288677;