16-56936702-G-A

Position:

• chr16-56936702-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014685.4(HERPUD1):​c.316G>A​(p.Glu106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HERPUD1 NM_014685.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19684508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERPUD1	NM_014685.4	c.316G>A	p.Glu106Lys	missense_variant	4/8	ENST00000439977.7
HERPUD1	NM_001010989.3	c.313G>A	p.Glu105Lys	missense_variant	4/8
HERPUD1	NM_001272103.2	c.316G>A	p.Glu106Lys	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERPUD1	ENST00000439977.7	c.316G>A	p.Glu106Lys	missense_variant	4/8	1	NM_014685.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 23, 2024

The c.316G>A (p.E106K) alteration is located in exon 4 (coding exon 4) of the HERPUD1 gene. This alteration results from a G to A substitution at nucleotide position 316, causing the glutamic acid (E) at amino acid position 106 to be replaced by a lysine (K). 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	0.068
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;T;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.74	N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.50	T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.69	P;D;P;.;.;.
Vest4		0.19
MutPred		0.24		Gain of ubiquitination at E106 (P = 9e-04);.;.;.;.;.;
MVP		0.66
MPC		0.26
ClinPred		0.49	T
GERP RS		6.2
Varity_R		0.20
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56970614;