chr2-211377467-A-C

Variant names:

• chr2-211377467-A-C
• rs11895168
• NM_005235.3:c.*6148T>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.*6148T>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 0.672 in 232,666 control chromosomes in the GnomAD database, including 52,834 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 0.68 (34940 hom., cov: 32)
  • Exomes 𝑓: 0.66 (17894 hom.)
• Consequence: ERBB4 NM_005235.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 15 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.751 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.*6148T>G		3_prime_UTR	Exon 28 of 28	NP_005226.1
	ERBB4	NM_001439005.1		c.*6148T>G		3_prime_UTR	Exon 28 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.*6148T>G		3_prime_UTR	Exon 27 of 27	NP_001036064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.*6148T>G		3_prime_UTR	Exon 28 of 28	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.*6148T>G		3_prime_UTR	Exon 27 of 27	ENSP00000403204.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102635 AN: 151896 Hom.: 34885 Cov.: 32

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.643

GnomAD4 exome AF: 0.664 AC: 53544 AN: 80652 Hom.: 17894 Cov.: 0 AF XY: 0.667 AC XY: 24753 AN XY: 37138

African (AFR) AF: 0.745 AC: 2867 AN: 3848

American (AMR) AF: 0.648 AC: 1609 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 3111 AN: 5072

East Asian (EAS) AF: 0.767 AC: 8657 AN: 11284

South Asian (SAS) AF: 0.741 AC: 516 AN: 696

European-Finnish (FIN) AF: 0.654 AC: 310 AN: 474

Middle Eastern (MID) AF: 0.647 AC: 317 AN: 490

European-Non Finnish (NFE) AF: 0.641 AC: 31794 AN: 49588

Other (OTH) AF: 0.650 AC: 4363 AN: 6716

GnomAD4 genome AF: 0.676 AC: 102755 AN: 152014 Hom.: 34940 Cov.: 32 AF XY: 0.678 AC XY: 50337 AN XY: 74284

African (AFR) AF: 0.745 AC: 30901 AN: 41490

American (AMR) AF: 0.649 AC: 9904 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2106 AN: 3470

East Asian (EAS) AF: 0.748 AC: 3853 AN: 5152

South Asian (SAS) AF: 0.772 AC: 3723 AN: 4822

European-Finnish (FIN) AF: 0.626 AC: 6621 AN: 10570

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.642 AC: 43610 AN: 67938

Other (OTH) AF: 0.643 AC: 1356 AN: 2110

Alfa AF: 0.651 Hom.: 25351

Bravo AF: 0.678

Asia WGS AF: 0.713 AC: 2477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.61
PhyloP100		0.15
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: rs11895168; hg19: chr2-212242192; COSMIC: COSV61502032;