chr4-88523885-C-T

Variant names:

• chr4-88523885-C-T
• rs78551699
• ENST00000512194:c.-273C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001375482.1(HERC3):​c.-135C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 577,660 control chromosomes in the GnomAD database, including 693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (219 hom., cov: 33)
  • Exomes 𝑓: 0.032 (474 hom.)
• Consequence: HERC3 NM_001375482.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14

Genes affected

HERC3 (HGNC:):

HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

PIGY-DT (HGNC:54080): (PIGY divergent transcript)

PYURF (HGNC:44317): (PIGY upstream open reading frame) The product of this gene, which is well-conserved, is encoded by the same bicistronic transcript that encodes phosphatidylinositol glycan anchor biosynthesis, class Y, but the two proteins are unrelated. This gene represents the protein encoded by the upstream open reading frame, while the protein encoded by the downstream open reading frame is represented by GeneID:84992. [provided by RefSeq, Aug 2012]

PIGY (HGNC:28213): (phosphatidylinositol glycan anchor biosynthesis class Y) The protein encoded by this gene is part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex which initiates the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized in the endoplasmic reticulum and serves as an anchor for many surface proteins. Proteins containing GPI anchors can have an important role in cell-cell interactions. The transcript for this gene is bicistronic. The downstream open reading frame encodes this GPI-GnT complex protein, while the upstream open reading frame encodes a protein with unknown function, as represented by GeneID:100996939. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-88523885-C-T is Benign according to our data. Variant chr4-88523885-C-T is described in ClinVar as [Benign]. Clinvar id is 1290155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYURF	NM_032906.5	c.-185G>A		upstream_gene_variant		ENST00000273968.5	NP_116295.1
PIGY	NM_001042616.3	c.-628G>A		upstream_gene_variant		ENST00000527353.2	NP_001036081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC3	ENST00000512194	c.-273C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 26	5		ENSP00000421021.2
HERC3	ENST00000512194	c.-273C>T		5_prime_UTR_variant	Exon 1 of 26	5		ENSP00000421021.2
PYURF	ENST00000273968.5	c.-185G>A		upstream_gene_variant		1	NM_032906.5	ENSP00000273968.4
PIGY	ENST00000527353.2	c.-628G>A		upstream_gene_variant		6	NM_001042616.3	ENSP00000432688.1

Frequencies

GnomAD3 genomes AF: 0.0418 AC: 6361 AN: 152212 Hom.: 219 Cov.: 33

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00964

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0363

GnomAD4 exome AF: 0.0320 AC: 13593 AN: 425330 Hom.: 474 Cov.: 5 AF XY: 0.0367 AC XY: 8142 AN XY: 221960

Gnomad4 AFR exome AF: 0.0824

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0107

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.00978

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0418 AC: 6365 AN: 152330 Hom.: 219 Cov.: 33 AF XY: 0.0423 AC XY: 3151 AN XY: 74494

Gnomad4 AFR AF: 0.0835

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00966

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0433 Hom.: 30

Bravo AF: 0.0406

Asia WGS AF: 0.0560 AC: 193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.3
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78551699; hg19: chr4-89445036;