Genetic Variant HERPUD1:c.*696G>A (chr16-56943986-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014685.4(HERPUD1):c.*696G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 172,048 control chromosomes in the GnomAD database, including 1,415 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1170 hom., cov: 32)

Exomes 𝑓: 0.14 ( 245 hom. )

Consequence

HERPUD1
NM_014685.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Publications

14 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERPUD1	NM_014685.4 link	c.*696G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000439977.7	NP_055500.1	Q15011-1Q53FP9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERPUD1	ENST00000439977.7 link	c.*696G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_014685.4	ENSP00000409555.2		Q15011-1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16069

AN:

152112

Hom.:

1161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.180

Gnomad EAS

AF:

0.279

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.120

GnomAD4 exome

AF:

0.143

AC:

2838

AN:

19818

Hom.:

245

Cov.:

AF XY:

0.145

AC XY:

1351

AN XY:

9308

show subpopulations

African (AFR)

AF:

0.0300

AC:

AN:

566

American (AMR)

AF:

0.169

AC:

140

AN:

826

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

195

AN:

1110

East Asian (EAS)

AF:

0.240

AC:

891

AN:

3708

South Asian (SAS)

AF:

0.172

AC:

AN:

360

European-Finnish (FIN)

AF:

0.128

AC:

AN:

250

Middle Eastern (MID)

AF:

0.123

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.112

AC:

1272

AN:

11372

Other (OTH)

AF:

0.142

AC:

215

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

117

233

350

466

583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.106

AC:

16074

AN:

152230

Hom.:

1170

Cov.:

AF XY:

0.110

AC XY:

8187

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0263

AC:

1093

AN:

41564

American (AMR)

AF:

0.194

AC:

2970

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

625

AN:

3470

East Asian (EAS)

AF:

0.279

AC:

1444

AN:

5174

South Asian (SAS)

AF:

0.163

AC:

786

AN:

4828

European-Finnish (FIN)

AF:

0.111

AC:

1181

AN:

10592

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.111

AC:

7574

AN:

68000

Other (OTH)

AF:

0.121

AC:

256

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

727

1453

2180

2906

3633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.115

Hom.:

2612

Bravo

AF:

0.108

Asia WGS

AF:

0.214

AC:

742

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.7

(source)

DANN

Benign

0.70

PhyloP100

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over