rs839517

Positions:

• chr2-211953052-G-A
• chr2-211953052-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.235-5436C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 151,790 control chromosomes in the GnomAD database, including 8,827 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8827 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.374

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.235-5436C>T		intron_variant		ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.235-5436C>T		intron_variant		1	NM_005235.3	ENSP00000342235	P4

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48659 AN: 151672 Hom.: 8792 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.329

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.321 AC: 48747 AN: 151790 Hom.: 8827 Cov.: 32 AF XY: 0.323 AC XY: 23965 AN XY: 74176

Gnomad4 AFR AF: 0.487

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.392

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.327

Alfa AF: 0.231 Hom.: 2207

Bravo AF: 0.336

Asia WGS AF: 0.385 AC: 1338 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.66

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: rs839517; hg19: chr2-212817777;