rs374767640

Positions:

• chr7-838940-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130965.3(SUN1):​c.220G>A​(p.Asp74Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,609,166 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: SUN1 NM_001130965.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.557

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 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=0.06317982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN1	NM_001130965.3	c.220G>A	p.Asp74Asn	missense_variant	2/19	ENST00000401592.6	NP_001124437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN1	ENST00000401592.6	c.220G>A	p.Asp74Asn	missense_variant	2/19	1	NM_001130965.3	ENSP00000384015	P3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000542 AC: 13 AN: 239900 Hom.: 0 AF XY: 0.0000613 AC XY: 8 AN XY: 130444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000730

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000398 AC: 58 AN: 1456844 Hom.: 1 Cov.: 31 AF XY: 0.0000469 AC XY: 34 AN XY: 724238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74494

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000497 AC: 6

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 461651). This variant has not been reported in the literature in individuals affected with SUN1-related conditions. This variant is present in population databases (rs374767640, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 74 of the SUN1 protein (p.Asp74Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.56
DANN	Benign	0.39
DEOGEN2	Benign	0.0068	.;.;.;.;T;T;T;.;T;T;.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.55	T;.;T;T;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L;.;.;.;.;.;.;.;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.25	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.096
Sift	Benign	0.96	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	.;B;.;.;.;.;.;.;.;.;.;.;B;.
Vest4		0.12
MVP		0.27
MPC		0.083
ClinPred		0.014	T
GERP RS		0.27
gMVP		0.13

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: rs374767640; hg19: chr7-878577;