rs3748962

Variant names:

• chr2-211387139-T-C
• rs3748962
• NM_005235.3:c.3195A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005235.3(ERBB4):​c.3195A>G​(p.Val1065Val) 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:7
• Conservation: PhyloP100: -1.59
• Publications: 33 publications found

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]

ERBB4 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 19

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1210024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.3195A>G	p.Val1065Val	synonymous	Exon 27 of 28	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.3165A>G	p.Val1055Val	synonymous	Exon 27 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.3147A>G	p.Val1049Val	synonymous	Exon 26 of 27	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3195A>G	p.Val1065Val	synonymous	Exon 27 of 28	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.3147A>G	p.Val1049Val	synonymous	Exon 26 of 27	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000260943.11	TSL:5	c.3117A>G	p.Val1039Val	synonymous	Exon 26 of 27	ENSP00000260943.7	Q15303-4

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

GnomAD2 exomes AF: 0.300 AC: 75209 AN: 250482 AF XY: 0.304

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 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

African (AFR) AF: 0.0876 AC: 2932 AN: 33462

American (AMR) AF: 0.260 AC: 11637 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8614 AN: 26124

East Asian (EAS) AF: 0.276 AC: 10941 AN: 39672

South Asian (SAS) AF: 0.265 AC: 22823 AN: 86182

European-Finnish (FIN) AF: 0.354 AC: 18894 AN: 53416

Middle Eastern (MID) AF: 0.316 AC: 1818 AN: 5748

European-Non Finnish (NFE) AF: 0.342 AC: 378923 AN: 1108340

Other (OTH) AF: 0.315 AC: 18996 AN: 60270

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

African (AFR) AF: 0.0999 AC: 4150 AN: 41540

American (AMR) AF: 0.255 AC: 3902 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1609 AN: 5158

South Asian (SAS) AF: 0.258 AC: 1246 AN: 4824

European-Finnish (FIN) AF: 0.352 AC: 3718 AN: 10550

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22950 AN: 67956

Other (OTH) AF: 0.265 AC: 559 AN: 2112

Alfa AF: 0.305 Hom.: 13617

Bravo AF: 0.247

Asia WGS AF: 0.238 AC: 827 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.330

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.48
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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