rs2518054

chr16-56943986-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014685.4(HERPUD1):c.*696G>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 0.11 in 172,048 control chromosomes in the GnomAD database, including 1,415 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 0.11 (1170 hom., cov: 32)
  • Exomes 𝑓: 0.14 (245 hom.)
• Consequence: HERPUD1 NM_014685.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

Genes affected

HERPUD1 (HGNC:13744): (homocysteine inducible ER protein with ubiquitin like domain 1) The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response. This response includes the inhibition of translation to prevent further accumulation of unfolded proteins, the increased expression of proteins involved in polypeptide folding, known as the unfolded protein response (UPR), and the destruction of misfolded proteins by the ER-associated protein degradation (ERAD) system. This gene may play a role in both UPR and ERAD. Its expression is induced by UPR and it has an ER stress response element in its promoter region while the encoded protein has an N-terminal ubiquitin-like domain which may interact with the ERAD system. This protein has been shown to interact with presenilin proteins and to increase the level of amyloid-beta protein following its overexpression. Alternative splicing of this gene produces multiple transcript variants encoding different isoforms. The full-length nature of all transcript variants has not been determined. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERPUD1	NM_014685.4	c.*696G>A		3_prime_UTR_variant	8/8	ENST00000439977.7
HERPUD1	NM_001010989.3	c.*696G>A		3_prime_UTR_variant	8/8
HERPUD1	NM_001272103.2	c.*887G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERPUD1	ENST00000439977.7	c.*696G>A		3_prime_UTR_variant	8/8	1	NM_014685.4	P4

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16069 AN: 152112 Hom.: 1161 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.120

GnomAD4 exome AF: 0.143 AC: 2838 AN: 19818 Hom.: 245 Cov.: 0 AF XY: 0.145 AC XY: 1351 AN XY: 9308

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.106 AC: 16074 AN: 152230 Hom.: 1170 Cov.: 32 AF XY: 0.110 AC XY: 8187 AN XY: 74422

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.121

Alfa AF: 0.116 Hom.: 2000

Bravo AF: 0.108

Asia WGS AF: 0.214 AC: 742 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	5.7
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2518054; hg19: chr16-56977898; COSMIC: COSV105178979; COSMIC: COSV105178979;