16-56935467-A-G

Position:

• chr16-56935467-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014685.4(HERPUD1):​c.292A>G​(p.Asn98Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HERPUD1 NM_014685.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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]

HERPUD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05414933).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERPUD1	NM_014685.4	c.292A>G	p.Asn98Asp	missense_variant	3/8	ENST00000439977.7	NP_055500.1
HERPUD1	NM_001010989.3	c.289A>G	p.Asn97Asp	missense_variant	3/8		NP_001010989.1
HERPUD1	NM_001272103.2	c.292A>G	p.Asn98Asp	missense_variant	3/8		NP_001259032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERPUD1	ENST00000439977.7	c.292A>G	p.Asn98Asp	missense_variant	3/8	1	NM_014685.4	ENSP00000409555.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000547 AC: 8 AN: 1461388 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2024

The c.292A>G (p.N98D) alteration is located in exon 3 (coding exon 3) of the HERPUD1 gene. This alteration results from a A to G substitution at nucleotide position 292, causing the asparagine (N) at amino acid position 98 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.9
DANN	Benign	0.74
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.54	T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.26	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.088
MVP		0.41
MPC		0.23
ClinPred		0.051	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.069
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs753350590; hg19: chr16-56969379;