rs144929525

chr7-843470-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001130965.3(SUN1):c.608C>T(p.Ala203Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,090 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A203T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (45 hom.)
• Consequence: SUN1 NM_001130965.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.72

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004375726).
• BP6: Variant 7-843470-C-T is Benign according to our data. Variant chr7-843470-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 461663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN1	NM_001130965.3	c.608C>T	p.Ala203Val	missense_variant	5/19	ENST00000401592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN1	ENST00000401592.6	c.608C>T	p.Ala203Val	missense_variant	5/19	1	NM_001130965.3	P3

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 742 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00465 AC: 1158 AN: 248890 Hom.: 3 AF XY: 0.00480 AC XY: 649 AN XY: 135262

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00627

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00685 AC: 10010 AN: 1461738 Hom.: 45 Cov.: 33 AF XY: 0.00669 AC XY: 4865 AN XY: 727168

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.00696

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00792

Gnomad4 OTH exome AF: 0.00759

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00447 AC XY: 333 AN XY: 74504

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00775

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00650 Hom.: 2

Bravo AF: 0.00538

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00181 AC: 7

ESP6500EA AF: 0.00741 AC: 61

ExAC AF: 0.00441 AC: 533

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00771

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 22, 2024

- -

SUN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

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	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	11
Dann	Uncertain	0.97
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T;.;T;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0044	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.060	T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.092	.;B;.;.;.;B;.
Vest4		0.10
MVP		0.12
MPC		0.087
ClinPred		0.0038	T
GERP RS		1.4
gMVP		0.20

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: rs144929525; hg19: chr7-883107; COSMIC: COSV61777872; COSMIC: COSV61777872;