7-860335-G-T

Variant summary

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

The NM_001130965.3(SUN1):​c.1732G>T​(p.Val578Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

SUN1
NM_001130965.3 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64
Variant links:
Genes affected
SUN1 (HGNC:18587): (Sad1 and UNC84 domain containing 1) This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

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=0.012440264).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SUN1NM_001130965.3 linkc.1732G>T p.Val578Leu missense_variant Exon 14 of 19 ENST00000401592.6 NP_001124437.1 O94901-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SUN1ENST00000401592.6 linkc.1732G>T p.Val578Leu missense_variant Exon 14 of 19 1 NM_001130965.3 ENSP00000384015.1 O94901-8

Frequencies

GnomAD3 genomes
AF:
0.000631
AC:
96
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00224
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000478
GnomAD3 exomes
AF:
0.0000925
AC:
23
AN:
248556
Hom.:
0
AF XY:
0.0000519
AC XY:
7
AN XY:
134976
show subpopulations
Gnomad AFR exome
AF:
0.00142
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:
0.00000890
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000451
AC:
66
AN:
1461858
Hom.:
0
Cov.:
33
AF XY:
0.0000316
AC XY:
23
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00182
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000630
AC:
96
AN:
152354
Hom.:
0
Cov.:
33
AF XY:
0.000550
AC XY:
41
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.00224
Gnomad4 AMR
AF:
0.000131
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:
0.000473
Alfa
AF:
0.000157
Hom.:
0
Bravo
AF:
0.000620
ESP6500AA
AF:
0.00193
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000149
AC:
18

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1
Feb 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 578 of the SUN1 protein (p.Val578Leu). This variant is present in population databases (rs201804636, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SUN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 530820). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
11
DANN
Benign
0.89
DEOGEN2
Benign
0.028
.;.;T;.;.;T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.56
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.81
.;T;T;T;T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.012
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N
REVEL
Benign
0.055
Sift
Benign
0.095
T;T;T;T;T;T
Sift4G
Uncertain
0.025
D;D;D;D;D;D
Polyphen
0.0060
B;.;.;.;B;.
Vest4
0.19
MVP
0.15
MPC
0.099
ClinPred
0.035
T
GERP RS
3.4
gMVP
0.43

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

LitVar

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

Other links and lift over

dbSNP: rs201804636; hg19: chr7-899972; API