7-860183-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130965.3(SUN1):c.1580G>T(p.Gly527Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,614,216 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G527G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (264 hom.)
• Consequence: SUN1 NM_001130965.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0340

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001863718).
• BP6: Variant 7-860183-G-T is Benign according to our data. Variant chr7-860183-G-T is described in ClinVar as [Benign]. Clinvar id is 461640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN1	NM_001130965.3	c.1580G>T	p.Gly527Val	missense_variant	14/19	ENST00000401592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN1	ENST00000401592.6	c.1580G>T	p.Gly527Val	missense_variant	14/19	1	NM_001130965.3	P3

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152218 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0104 AC: 2602 AN: 249518 Hom.: 186 AF XY: 0.00968 AC XY: 1311 AN XY: 135384

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00316 AC: 4614 AN: 1461880 Hom.: 264 Cov.: 33 AF XY: 0.00308 AC XY: 2241 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00470 AC: 716 AN: 152336 Hom.: 45 Cov.: 33 AF XY: 0.00529 AC XY: 394 AN XY: 74490

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00485 Hom.: 64

Bravo AF: 0.00595

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00971 AC: 1174

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

SUN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	6.1
Dann	Benign	0.94
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0019	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	P;P;P;P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Benign	0.084
Sift	Uncertain	0.011	D;T;D;D;D;T
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.97	D;.;.;.;D;.
Vest4		0.24
MPC		0.14
ClinPred		0.042	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.21

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

Other links and lift over

dbSNP: rs77058871; hg19: chr7-899820; COSMIC: COSV67451309;