17-39696795-C-T

Variant names:

• chr17-39696795-C-T
• rs2643194
• ENST00000578199.5:c.-18+1614C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000578199.5(ERBB2):​c.-18+1614C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 152,144 control chromosomes in the GnomAD database, including 34,138 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 0.67 (34098 hom., cov: 31)
  • Exomes 𝑓: 0.64 (40 hom.)
• Consequence: ERBB2 ENST00000578199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.965
• Publications: 14 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]

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-24+1614C>T		intron_variant	Intron 4 of 30		NP_001276865.1
ERBB2	NM_001005862.3	c.-18+1614C>T		intron_variant	Intron 4 of 29		NP_001005862.1
ERBB2	NM_001382782.1	c.-18+1614C>T		intron_variant	Intron 4 of 29		NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+1614C>T		intron_variant	Intron 4 of 17	1		ENSP00000462808.1
PGAP3	ENST00000584856.1	c.-325G>A		5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000463785.1
ERBB2	ENST00000406381.6	c.-18+1614C>T		intron_variant	Intron 1 of 26	5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-69+1614C>T		intron_variant	Intron 4 of 30	2		ENSP00000462438.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101223 AN: 151834 Hom.: 34040 Cov.: 31

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.659

GnomAD4 exome AF: 0.635 AC: 122 AN: 192 Hom.: 40 Cov.: 0 AF XY: 0.669 AC XY: 87 AN XY: 130

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 4 AN: 8

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 0.571 AC: 16 AN: 28

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.646 AC: 84 AN: 130

Other (OTH) AF: 0.750 AC: 12 AN: 16

GnomAD4 genome AF: 0.667 AC: 101347 AN: 151952 Hom.: 34098 Cov.: 31 AF XY: 0.665 AC XY: 49385 AN XY: 74262

African (AFR) AF: 0.667 AC: 27639 AN: 41414

American (AMR) AF: 0.602 AC: 9195 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2454 AN: 3470

East Asian (EAS) AF: 0.400 AC: 2066 AN: 5164

South Asian (SAS) AF: 0.734 AC: 3532 AN: 4810

European-Finnish (FIN) AF: 0.709 AC: 7486 AN: 10558

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46652 AN: 67948

Other (OTH) AF: 0.661 AC: 1394 AN: 2110

Alfa AF: 0.680 Hom.: 11996

Bravo AF: 0.654

Asia WGS AF: 0.640 AC: 2227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.66
PhyloP100		-0.96
PromoterAI		-0.0044	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2643194; hg19: chr17-37853048;