12-56076841-C-T

Variant names:

• chr12-56076841-C-T
• rs11171739
• ENST00000643266.1:c.-138C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000643266.1(ERBB3):c.-138C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: ENST00000643266.1 is not a MANE Select or MANE Plus Clinical transcript for ERBB3; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.502 (AC=75,779) in the gnomAD database across 150,900 control chromosomes, including 21,507 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.754. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (21479 hom., cov: 26)
  • Exomes 𝑓: 0.64 (28 hom.)
• Consequence: ERBB3 ENST00000643266.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 156 publications found

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]

ERBB3 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7535 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000643266.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ERBB3 ENST00000643266.1		c.-138C>T	5_prime_UTR	Exon 1 of 2	Prot: ENSP00000495453.1 UniProt:
	ERBB3 ENST00000643518.1		n.-71C>T	upstream_gene	N/A	Prot:

ERBB3 ENST00000643266.1

HGVSc / HGVSpc.-138C>T

Exon rankExon 1 of 2

5_prime_UTR

Prot: ENSP00000495453.1UniProt: A0A2R8Y6T4

ERBB3 ENST00000643518.1

HGVSc / HGVSpn.-71C>T

Exon rankN/A

upstream_gene

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.502	AC:75694	Hom:21476	AN:150664	Cov:26
GnomAD4 exome	AF: 0.644	AC:76	Hom:28	AN:118	Cov:0
GnomAD4 genome	AF: 0.502	AC:75703	Hom:21479	AN:150782	Cov:26
TOPMed (Bravo)	AF: 0.493	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.566	AC:359490	Hom:105654	AN:635162	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.520	AC:1218	Hom:320	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.756	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.573	AC:172	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.729	AC:2531	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.774	AC:5592	Hom:	AN:7224	Cov:
Qatari Genome	AF: 0.631	AC:111	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.798	AC:95148	Hom:37920	AN:119182	Cov:
Turkish Variome	AF: 0.676	AC:1045	Hom:347	AN:1546	Cov:
UK10K	AF: 0.574	AC:4341	Hom:	AN:7562	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.144	3259	22660	0.0620	1805	29126

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.0
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.7
DANN	Benign	0.54
GPN-Star LLR	N/A	-0.58
GPN-Star score	N/A	0.58
PhyloP100	Benign	0.071
PromoterAI	N/A	-0.016	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Pathogenic	0.58
Pangolin gain	Pathogenic	0.58	Position offset: 6

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs11171739;

hg19: chr12-56470625;

COSMIC: COSV57257946;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar