rs4252665

Variant names:

• chr17-39729130-C-T
• rs4252665
• NM_032339.5:c.*392G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_032339.5(MIEN1):​c.*392G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 219,790 control chromosomes in the GnomAD database, including 134 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 0.028 (87 hom., cov: 32)
  • Exomes 𝑓: 0.029 (47 hom.)
• Consequence: MIEN1 NM_032339.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 14 publications found

Genes affected

MIEN1 (HGNC:28230): (migration and invasion enhancer 1) Involved in negative regulation of apoptotic process; positive regulation of cell migration; and positive regulation of filopodium assembly. Located in several cellular components, including centriolar satellite; cytosol; and nucleoplasm. Is intrinsic component of the cytoplasmic side of the plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0278 (4232/152210) while in subpopulation NFE AF = 0.0424 (2882/68018). AF 95% confidence interval is 0.0411. There are 87 homozygotes in GnomAd4. There are 2035 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 87 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIEN1	NM_032339.5	c.*392G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000394231.8	NP_115715.3
MIEN1	NM_001330206.2	c.*468G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001317135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIEN1	ENST00000394231.8	c.*392G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_032339.5	ENSP00000377778.3

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4232 AN: 152092 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00732

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0292 AC: 1976 AN: 67580 Hom.: 47 Cov.: 0 AF XY: 0.0280 AC XY: 994 AN XY: 35490

African (AFR) AF: 0.00557 AC: 11 AN: 1976

American (AMR) AF: 0.0259 AC: 104 AN: 4012

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 19 AN: 1894

East Asian (EAS) AF: 0.00136 AC: 6 AN: 4404

South Asian (SAS) AF: 0.0170 AC: 152 AN: 8960

European-Finnish (FIN) AF: 0.0528 AC: 102 AN: 1932

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.0365 AC: 1476 AN: 40448

Other (OTH) AF: 0.0289 AC: 105 AN: 3638

GnomAD4 genome AF: 0.0278 AC: 4232 AN: 152210 Hom.: 87 Cov.: 32 AF XY: 0.0274 AC XY: 2035 AN XY: 74400

African (AFR) AF: 0.00729 AC: 303 AN: 41538

American (AMR) AF: 0.0200 AC: 305 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4814

European-Finnish (FIN) AF: 0.0515 AC: 546 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2882 AN: 68018

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0368 Hom.: 294

Bravo AF: 0.0239

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.75
PhyloP100		0.10

Splicing

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

Other links and lift over

dbSNP: rs4252665; hg19: chr17-37885383;