7-35694315-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022373.5(HERPUD2):​c.16A>T​(p.Met6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M6T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

HERPUD2
NM_022373.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0109114945).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HERPUD2NM_022373.5 linkuse as main transcriptc.16A>T p.Met6Leu missense_variant 2/9 ENST00000311350.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HERPUD2ENST00000311350.8 linkuse as main transcriptc.16A>T p.Met6Leu missense_variant 2/91 NM_022373.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000289
AC:
44
AN:
152132
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00106
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251438
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00141
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000289
AC:
44
AN:
152250
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00106
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000629
Hom.:
0
Bravo
AF:
0.000359
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12

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 submitterclinical testingAmbry GeneticsOct 03, 2022The c.16A>T (p.M6L) alteration is located in exon 2 (coding exon 1) of the HERPUD2 gene. This alteration results from a A to T substitution at nucleotide position 16, causing the methionine (M) at amino acid position 6 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
Benign
0.11
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
18
DANN
Benign
0.93
DEOGEN2
Benign
0.00084
T;T;.;.;T;.
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.56
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.80
.;T;T;T;T;.
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.011
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N;.;.;.;.
MutationTaster
Benign
0.68
N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.73
N;N;N;N;N;.
REVEL
Benign
0.086
Sift
Benign
0.33
T;T;T;T;T;.
Sift4G
Benign
1.0
T;T;T;.;.;.
Polyphen
0.0
B;B;.;.;.;.
Vest4
0.15
MutPred
0.23
Gain of catalytic residue at M6 (P = 0.0244);Gain of catalytic residue at M6 (P = 0.0244);Gain of catalytic residue at M6 (P = 0.0244);Gain of catalytic residue at M6 (P = 0.0244);Gain of catalytic residue at M6 (P = 0.0244);Gain of catalytic residue at M6 (P = 0.0244);
MVP
0.26
MPC
0.27
ClinPred
0.014
T
GERP RS
1.2
Varity_R
0.10
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs144332852; hg19: chr7-35733925; API