rs114015310

chr7-860249-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130965.3(SUN1):c.1646C>T(p.Thr549Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,614,222 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T549T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (51 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: SUN1 NM_001130965.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.559

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=0.0023887753).
• BP6: Variant 7-860249-C-T is Benign according to our data. Variant chr7-860249-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 461642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1816/152340) while in subpopulation AFR AF= 0.0418 (1739/41578). AF 95% confidence interval is 0.0402. There are 51 homozygotes in gnomad4. There are 899 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN1	NM_001130965.3	c.1646C>T	p.Thr549Met	missense_variant	14/19	ENST00000401592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN1	ENST00000401592.6	c.1646C>T	p.Thr549Met	missense_variant	14/19	1	NM_001130965.3	P3

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152222 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00272 AC: 679 AN: 249498 Hom.: 19 AF XY: 0.00206 AC XY: 279 AN XY: 135390

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00118 AC: 1722 AN: 1461882 Hom.: 36 Cov.: 33 AF XY: 0.00101 AC XY: 734 AN XY: 727246

Gnomad4 AFR exome AF: 0.0429

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.0119 AC: 1816 AN: 152340 Hom.: 51 Cov.: 33 AF XY: 0.0121 AC XY: 899 AN XY: 74496

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00258 Hom.: 10

Bravo AF: 0.0127

ESP6500AA AF: 0.0362 AC: 151

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00349 AC: 423

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely 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 29, 2024

- -

SUN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as likely 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	-0.58
Cadd	Benign	0.45
Dann	Benign	0.95
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.93	N;N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.075	T;T;T;T;T;T
Sift4G	Benign	0.073	T;T;T;T;T;T
Polyphen		0.0060	B;.;.;.;B;.
Vest4		0.17
MVP		0.13
MPC		0.088
ClinPred		0.0013	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs114015310; hg19: chr7-899886; COSMIC: COSV67450967;