rs3748962

chr2-211387139-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005235.3(ERBB4):c.3195A>G(p.Val1065=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,610,022 control chromosomes in the GnomAD database, including 85,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6088 hom., cov: 32)
  • Exomes 𝑓: 0.33 (79755 hom.)
• Consequence: ERBB4 NM_005235.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.59

Genes affected

ERBB4 (HGNC:3432): (erb-b2 receptor tyrosine kinase 4) This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-211387139-T-C is Benign according to our data. Variant chr2-211387139-T-C is described in ClinVar as [Benign]. Clinvar id is 1210024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-211387139-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB4	NM_005235.3	c.3195A>G	p.Val1065=	synonymous_variant	27/28	ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.3195A>G	p.Val1065=	synonymous_variant	27/28	1	NM_005235.3	P4
ERBB4	ENST00000436443.5	c.3147A>G	p.Val1049=	synonymous_variant	26/27	1		A1
ERBB4	ENST00000260943.11	c.3117A>G	p.Val1039=	synonymous_variant	26/27	5

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39631 AN: 151972 Hom.: 6091 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.300 AC: 75209 AN: 250482 Hom.: 12070 AF XY: 0.304 AC XY: 41161 AN XY: 135438

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.311

Gnomad SAS exome AF: 0.263

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.326 AC: 475578 AN: 1457930 Hom.: 79755 Cov.: 32 AF XY: 0.326 AC XY: 236382 AN XY: 725530

Gnomad4 AFR exome AF: 0.0876

Gnomad4 AMR exome AF: 0.260

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.276

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.261 AC: 39628 AN: 152092 Hom.: 6088 Cov.: 32 AF XY: 0.260 AC XY: 19312 AN XY: 74336

Gnomad4 AFR AF: 0.0999

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.338

Gnomad4 OTH AF: 0.265

Alfa AF: 0.312 Hom.: 10564

Bravo AF: 0.247

Asia WGS AF: 0.238 AC: 827 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.330

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.53
Dann	Benign	0.48

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: rs3748962; hg19: chr2-212251864; COSMIC: COSV61463116;