NM_005235.3:c.*5329A>G

Variant names:

• chr2-211378286-T-C
• rs16845990
• NM_005235.3:c.*5329A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.*5329A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 232,502 control chromosomes in the GnomAD database, including 18,313 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 0.39 (12007 hom., cov: 32)
  • Exomes 𝑓: 0.39 (6306 hom.)
• Consequence: ERBB4 NM_005235.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.581 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.*5329A>G		3_prime_UTR	Exon 28 of 28	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.*5329A>G		3_prime_UTR	Exon 28 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.*5329A>G		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.*5329A>G		3_prime_UTR	Exon 28 of 28	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.*5329A>G		3_prime_UTR	Exon 27 of 27	ENSP00000403204.1	Q15303-3

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59489 AN: 151834 Hom.: 11979 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.390 AC: 31445 AN: 80550 Hom.: 6306 Cov.: 0 AF XY: 0.388 AC XY: 14402 AN XY: 37082

African (AFR) AF: 0.449 AC: 1732 AN: 3858

American (AMR) AF: 0.399 AC: 990 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1985 AN: 5082

East Asian (EAS) AF: 0.527 AC: 5999 AN: 11380

South Asian (SAS) AF: 0.612 AC: 427 AN: 698

European-Finnish (FIN) AF: 0.303 AC: 77 AN: 254

Middle Eastern (MID) AF: 0.404 AC: 197 AN: 488

European-Non Finnish (NFE) AF: 0.354 AC: 17549 AN: 49576

Other (OTH) AF: 0.370 AC: 2489 AN: 6730

GnomAD4 genome AF: 0.392 AC: 59568 AN: 151952 Hom.: 12007 Cov.: 32 AF XY: 0.395 AC XY: 29317 AN XY: 74250

African (AFR) AF: 0.453 AC: 18786 AN: 41448

American (AMR) AF: 0.398 AC: 6070 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1311 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2324 AN: 5140

South Asian (SAS) AF: 0.600 AC: 2889 AN: 4818

European-Finnish (FIN) AF: 0.290 AC: 3073 AN: 10588

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23944 AN: 67926

Other (OTH) AF: 0.372 AC: 781 AN: 2100

Alfa AF: 0.365 Hom.: 11869

Bravo AF: 0.398

Asia WGS AF: 0.505 AC: 1755 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.70
PhyloP100		1.9
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: rs16845990; hg19: chr2-212243011;