2-211377000-C-T

Variant names:

• chr2-211377000-C-T
• rs1595066
• NM_005235.3:c.*6615G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005235.3(ERBB4):​c.*6615G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 232,700 control chromosomes in the GnomAD database, including 11,738 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 0.29 (6937 hom., cov: 32)
  • Exomes 𝑓: 0.34 (4801 hom.)
• Consequence: ERBB4 NM_005235.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 23 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.552 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.*6615G>A		3_prime_UTR	Exon 28 of 28	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.*6615G>A		3_prime_UTR	Exon 28 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.*6615G>A		3_prime_UTR	Exon 27 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.*6615G>A		3_prime_UTR	Exon 28 of 28	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.*6615G>A		3_prime_UTR	Exon 27 of 27	ENSP00000403204.1	Q15303-3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43779 AN: 151748 Hom.: 6930 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.338 AC: 27349 AN: 80834 Hom.: 4801 Cov.: 0 AF XY: 0.340 AC XY: 12634 AN XY: 37212

African (AFR) AF: 0.160 AC: 618 AN: 3858

American (AMR) AF: 0.311 AC: 775 AN: 2490

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1663 AN: 5076

East Asian (EAS) AF: 0.447 AC: 5086 AN: 11390

South Asian (SAS) AF: 0.583 AC: 407 AN: 698

European-Finnish (FIN) AF: 0.286 AC: 146 AN: 510

Middle Eastern (MID) AF: 0.351 AC: 172 AN: 490

European-Non Finnish (NFE) AF: 0.331 AC: 16411 AN: 49600

Other (OTH) AF: 0.308 AC: 2071 AN: 6722

GnomAD4 genome AF: 0.288 AC: 43799 AN: 151866 Hom.: 6937 Cov.: 32 AF XY: 0.293 AC XY: 21767 AN XY: 74222

African (AFR) AF: 0.167 AC: 6909 AN: 41420

American (AMR) AF: 0.309 AC: 4708 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3472

East Asian (EAS) AF: 0.356 AC: 1823 AN: 5124

South Asian (SAS) AF: 0.569 AC: 2744 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3049 AN: 10554

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22573 AN: 67918

Other (OTH) AF: 0.277 AC: 584 AN: 2108

Alfa AF: 0.333 Hom.: 5306

Bravo AF: 0.278

Asia WGS AF: 0.432 AC: 1497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		3.5
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: rs1595066; hg19: chr2-212241725; COSMIC: COSV61530940;