2-211383728-C-T

Position:

• chr2-211383728-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_005235.3(ERBB4):​c.3814G>A​(p.Gly1272Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ERBB4 NM_005235.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.39

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 2-211383728-C-T is Pathogenic according to our data. Variant chr2-211383728-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976654.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.3814G>A	p.Gly1272Arg	missense_variant	28/28	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.3814G>A	p.Gly1272Arg	missense_variant	28/28	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.3766G>A	p.Gly1256Arg	missense_variant	27/27	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.3736G>A	p.Gly1246Arg	missense_variant	27/27	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Jul 31, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	.;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0040	.;D;D
Polyphen		0.99, 1.0	.;D;D
Vest4		0.68, 0.66
MutPred		0.59		.;Gain of MoRF binding (P = 0.012);.;
MVP		0.90
MPC		1.2
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.64
gMVP		0.71

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: rs371332509; hg19: chr2-212248453; COSMIC: COSV61501971;