rs144929525

Variant names:

• chr7-843470-C-T
• rs144929525
• NM_001130965.3:c.608C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:3
• Conservation: PhyloP100: 1.72
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 461663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130965.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN1	NM_001130965.3	MANE Select	c.608C>T	p.Ala203Val	missense	Exon 5 of 19	NP_001124437.1
	SUN1	NM_001367651.1		c.827C>T	p.Ala276Val	missense	Exon 6 of 22	NP_001354580.1
	SUN1	NM_001367705.1		c.608C>T	p.Ala203Val	missense	Exon 6 of 23	NP_001354634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN1	ENST00000401592.6	TSL:1 MANE Select	c.608C>T	p.Ala203Val	missense	Exon 5 of 19	ENSP00000384015.1
	SUN1	ENST00000429178.5	TSL:1	c.101C>T	p.Ala34Val	missense	Exon 1 of 17	ENSP00000409909.1
	SUN1	ENST00000457378.6	TSL:1	c.671C>T	p.Ala224Val	missense	Exon 7 of 7	ENSP00000395952.2

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

GnomAD2 exomes AF: 0.00465 AC: 1158 AN: 248890 AF XY: 0.00480

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 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

African (AFR) AF: 0.00131 AC: 44 AN: 33480

American (AMR) AF: 0.00494 AC: 221 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86258

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53386

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00792 AC: 8807 AN: 1111908

Other (OTH) AF: 0.00759 AC: 458 AN: 60382

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

African (AFR) AF: 0.00180 AC: 75 AN: 41582

American (AMR) AF: 0.00523 AC: 80 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00775 AC: 527 AN: 68038

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00609 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Emery-Dreifuss muscular dystrophy (1)
-	-	1	not provided (1)
-	-	1	SUN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Uncertain	0.97
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		1.7
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.048
Sift	Benign	0.060	T
Sift4G	Benign	0.14	T
Polyphen		0.092	B
Vest4		0.10
MVP		0.12
MPC		0.087
ClinPred		0.0038	T
GERP RS		1.4
PromoterAI		0.023	Neutral
gMVP		0.20
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

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