Variant 16-56939282-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_014685.4(HERPUD1):c.477C>G(p.Phe159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

HERPUD1
NM_014685.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HERPUD1	NM_014685.4 linkuse as main transcript	c.477C>G	p.Phe159Leu	missense_variant	5/8	ENST00000439977.7	NP_055500.1
HERPUD1	NM_001010989.3 linkuse as main transcript	c.474C>G	p.Phe158Leu	missense_variant	5/8		NP_001010989.1
HERPUD1	NM_001272103.2 linkuse as main transcript	c.477C>G	p.Phe159Leu	missense_variant	5/8		NP_001259032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERPUD1	ENST00000439977.7 linkuse as main transcript	c.477C>G	p.Phe159Leu	missense_variant	5/8	1	NM_014685.4	ENSP00000409555	P4	Q15011-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727232

show subpopulations

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:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.477C>G (p.F159L) alteration is located in exon 5 (coding exon 5) of the HERPUD1 gene. This alteration results from a C to G substitution at nucleotide position 477, causing the phenylalanine (F) at amino acid position 159 to be replaced by a leucine (L). 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

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.029

D;D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D;D

Polyphen

0.86

P;P;.;.;.

Vest4

0.44

MutPred

0.55

Gain of catalytic residue at F159 (P = 0.0159);.;.;.;.;

MVP

0.45

MPC

0.43

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Varity_R

0.36

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over