rs2217332

chr16-56935236-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.149G>A(p.Arg50His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,607,832 control chromosomes in the GnomAD database, including 17,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1582 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15542 hom.)
• Consequence: HERPUD1 NM_014685.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001747
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101

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 (MetaRNN=0.0019485354).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERPUD1	NM_014685.4	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	2/8	ENST00000439977.7
HERPUD1	NM_001010989.3	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	2/8
HERPUD1	NM_001272103.2	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERPUD1	ENST00000439977.7	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	2/8	1	NM_014685.4	P4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21382 AN: 152056 Hom.: 1581 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0765

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.150 AC: 37626 AN: 251376 Hom.: 2999 AF XY: 0.153 AC XY: 20727 AN XY: 135852

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.0761

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.143 AC: 208523 AN: 1455658 Hom.: 15542 Cov.: 30 AF XY: 0.145 AC XY: 105312 AN XY: 724622

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.0766

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.141 AC: 21392 AN: 152174 Hom.: 1582 Cov.: 32 AF XY: 0.142 AC XY: 10561 AN XY: 74398

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.0767

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.148

Alfa AF: 0.147 Hom.: 4361

Bravo AF: 0.141

TwinsUK AF: 0.144 AC: 534

ALSPAC AF: 0.143 AC: 552

ESP6500AA AF: 0.128 AC: 564

ESP6500EA AF: 0.156 AC: 1340

ExAC AF: 0.150 AC: 18195

Asia WGS AF: 0.150 AC: 521 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Benign	0.91
DEOGEN2	Benign	0.13	T;.;.;.;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.45	T;T;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;L;L;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.25	T;T;T;T;D;D
Sift4G	Benign	0.58	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;.;.
Vest4		0.055
MPC		0.25
ClinPred		0.0015	T
GERP RS		3.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.050
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.010
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: rs2217332; hg19: chr16-56969148; COSMIC: COSV55861700; COSMIC: COSV55861700;