rs755855285

Positions:

• chr12-56102035-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2 PP5 BP4

The NM_001982.4(ERBB3):​c.4009G>A​(p.Ala1337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000082 in 1,610,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 2.65

Genes affected

ERBB3 (HGNC:3431): (erb-b2 receptor tyrosine kinase 3) This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ENSG00000257411 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB3. . Gene score misZ 1.3904 (greater than the threshold 3.09). Trascript score misZ 3.2897 (greater than threshold 3.09). GenCC has associacion of gene with Hirschsprung disease, lethal congenital contracture syndrome 2.
• PP5: Variant 12-56102035-G-A is Pathogenic according to our data. Variant chr12-56102035-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253223.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10978612). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.4009G>A	p.Ala1337Thr	missense_variant	28/28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3832G>A	p.Ala1278Thr	missense_variant	28/28		XP_047284456.1
ERBB3	XM_047428501.1	c.3832G>A	p.Ala1278Thr	missense_variant	28/28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.4009G>A	p.Ala1337Thr	missense_variant	28/28	1	NM_001982.4	ENSP00000267101.4
ENSG00000257411	ENST00000548861.2	c.31+674G>A		intron_variant		5		ENSP00000449770.3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151848 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 27 AN: 247050 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134258

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000768 AC: 112 AN: 1458680 Hom.: 0 Cov.: 33 AF XY: 0.0000799 AC XY: 58 AN XY: 725848

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

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: 0.0000935

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151848 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74136

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Erythroleukemia, familial, susceptibility to Pathogenic:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Oct 16, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 24, 2023

Variant summary: ERBB3 c.4009G>A (p.Ala1337Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 247050 control chromosomes (gnomAD). To our knowledge, c.4009G>A has not been reported in the literature in individuals affected with Lethal congenital contracture syndrome 2. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Braunstein_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27416908). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.30	T;.;T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.20	N;N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.46	T;T;.;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.090
MVP		0.82
MPC		0.31
ClinPred		0.54	D
GERP RS		4.4
Varity_R		0.067
gMVP		0.35

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: rs755855285; hg19: chr12-56495819;