rs3213837

chr5-66025483-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001253697.2(ERBIN):c.821C>T(p.Ser274Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,602,994 control chromosomes in the GnomAD database, including 19,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S274S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1411 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18520 hom.)
• Consequence: ERBIN NM_001253697.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015951693).
• BP6: Variant 5-66025483-C-T is Benign according to our data. Variant chr5-66025483-C-T is described in ClinVar as [Benign]. Clinvar id is 1165181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBIN	NM_001253697.2	c.821C>T	p.Ser274Leu	missense_variant	11/26	ENST00000284037.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBIN	ENST00000284037.10	c.821C>T	p.Ser274Leu	missense_variant	11/26	1	NM_001253697.2	A1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18257 AN: 151674 Hom.: 1414 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0967

Gnomad EAS AF: 0.0960

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.153 AC: 38297 AN: 250684 Hom.: 3343 AF XY: 0.158 AC XY: 21414 AN XY: 135592

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0948

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.154 AC: 223650 AN: 1451202 Hom.: 18520 Cov.: 29 AF XY: 0.157 AC XY: 113606 AN XY: 722652

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0886

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.120 AC: 18249 AN: 151792 Hom.: 1411 Cov.: 32 AF XY: 0.121 AC XY: 9004 AN XY: 74180

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.0967

Gnomad4 EAS AF: 0.0959

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.105

Alfa AF: 0.146 Hom.: 4106

Bravo AF: 0.113

TwinsUK AF: 0.154 AC: 571

ALSPAC AF: 0.162 AC: 624

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.156 AC: 1344

ExAC AF: 0.154 AC: 18754

Asia WGS AF: 0.180 AC: 627 AN: 3476

EpiCase AF: 0.147

EpiControl AF: 0.144

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	22
Dann	Benign	0.84
DEOGEN2	Benign	0.036	T;.;T;.;.;.;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;.
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.00059	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N;N;N
REVEL	Benign	0.034
Sift	Benign	0.55	T;T;T;T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;.;.;B
Vest4		0.12
MPC		0.061
ClinPred		0.0042	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.40

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

Other links and lift over

dbSNP: rs3213837; hg19: chr5-65321311; COSMIC: COSV52316516; COSMIC: COSV52316516;