rs1039589946

Variant names:

• chr17-39700248-G-A
• rs1039589946
• NM_004448.4:c.10G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39700248-G-A
• chr17-39700248-G-C
• chr17-39700248-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004448.4(ERBB2):​c.10G>A​(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,290,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.600
• Publications: 7 publications found

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

ERBB2 Gene-Disease associations (from GenCC):

• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lung cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glioma susceptibility 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• visceral neuropathy, familial, 2, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2956599).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004448.4. 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
	ERBB2	NM_004448.4	MANE Select	c.10G>A	p.Ala4Thr	missense	Exon 1 of 27	NP_004439.2	P04626-1
	ERBB2	NM_001382784.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 28	NP_001369713.1
	ERBB2	NM_001382785.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 28	NP_001369714.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.10G>A	p.Ala4Thr	missense	Exon 1 of 27	ENSP00000269571.4	P04626-1
	ERBB2	ENST00000584450.5	TSL:1	c.10G>A	p.Ala4Thr	missense	Exon 1 of 26	ENSP00000463714.1	J3QLU9
	ERBB2	ENST00000578199.5	TSL:1	c.-18+5067G>A		intron	N/A	ENSP00000462808.1	F5H1T4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1290614 Hom.: 0 Cov.: 31 AF XY: 0.00000158 AC XY: 1 AN XY: 634874

African (AFR) AF: 0.00 AC: 0 AN: 26262

American (AMR) AF: 0.00 AC: 0 AN: 23438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22340

East Asian (EAS) AF: 0.00 AC: 0 AN: 27988

South Asian (SAS) AF: 0.00 AC: 0 AN: 67034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3780

European-Non Finnish (NFE) AF: 9.68e-7 AC: 1 AN: 1033228

Other (OTH) AF: 0.00 AC: 0 AN: 53234

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.60
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.26	T
Polyphen		0.036	B
Vest4		0.11
MutPred		0.41		Loss of helix (P = 0.0041)
MVP		0.74
MPC		0.33
ClinPred		0.46	T
GERP RS		2.4
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1039589946; hg19: chr17-37856501;