Genetic Variant SUN1:p.Val578Leu (chr7-860335-G-T) – ACMG Classification: Likely_benign (-2 pts)

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

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]

SUN1 links:

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
SUN1	NM_001130965.3 link	c.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
SUN1	ENST00000401592.6 link	c.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:

AN:

152236

Hom.:

Cov.:

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:

AN:

248556

Hom.:

AF XY:

0.0000519

AC XY:

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:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

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:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

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.:

Bravo

AF:

0.000620

ESP6500AA

AF:

0.00193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.028

.;.;T;.;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.81

.;T;T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.28

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

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.

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