Genetic Variant HERPUD2:p.Val85Ile (chr7-35670301-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_022373.5(HERPUD2):c.253G>A(p.Val85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,551,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

HERPUD2
NM_022373.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

Variant links:

Genes affected

HERPUD2 (HGNC:21915): (HERPUD family member 2) Predicted to be involved in endoplasmic reticulum unfolded protein response. Predicted to act upstream of or within spermatogenesis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

HERPUD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERPUD2	NM_022373.5 link	c.253G>A	p.Val85Ile	missense_variant	Exon 4 of 9	ENST00000311350.8	NP_071768.3	Q9BSE4A0A024RA77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERPUD2	ENST00000311350.8 link	c.253G>A	p.Val85Ile	missense_variant	Exon 4 of 9	1	NM_022373.5	ENSP00000310729.3		Q9BSE4

Frequencies

GnomAD3 genomes

AF:

0.0000674

AC:

AN:

148334

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000874

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000743

Gnomad OTH

AF:

0.000492

GnomAD3 exomes

AF:

0.0000731

AC:

AN:

232426

Hom.:

AF XY:

0.0000949

AC XY:

AN XY:

126390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000625

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000838

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.0000435

AC:

AN:

1402912

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

698170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000640

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000767

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000177

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000674

AC:

AN:

148334

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

72028

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000874

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000218

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000743

Gnomad4 OTH

AF:

0.000492

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>A (p.V85I) alteration is located in exon 4 (coding exon 3) of the HERPUD2 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the valine (V) at amino acid position 85 to be replaced by an isoleucine (I). 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

Uncertain

0.44

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

T;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.4

M;M;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.88

N;N;N

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;T

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.59

MutPred

0.53

Loss of catalytic residue at V85 (P = 0.0477);Loss of catalytic residue at V85 (P = 0.0477);.;

MVP

0.53

MPC

0.83

ClinPred

0.87

GERP RS

3.8

Varity_R

0.49

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: -26

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