NM_001130965.3:c.78-3T>C

Variant names:

• chr7-838795-T-C
• rs77466627
• NM_001130965.3:c.78-3T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001130965.3(SUN1):​c.78-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,538,870 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: SUN1 NM_001130965.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001835
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0490
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-838795-T-C is Benign according to our data. Variant chr7-838795-T-C is described in ClinVar as Benign. ClinVar VariationId is 461668.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00154 (234/152364) while in subpopulation EAS AF = 0.0376 (195/5188). AF 95% confidence interval is 0.0333. There are 8 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN1	NM_001130965.3	MANE Select	c.78-3T>C		splice_region intron	N/A	NP_001124437.1
	SUN1	NM_001367651.1		c.297-3T>C		splice_region intron	N/A	NP_001354580.1
	SUN1	NM_001367705.1		c.78-3T>C		splice_region intron	N/A	NP_001354634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN1	ENST00000401592.6	TSL:1 MANE Select	c.78-3T>C		splice_region intron	N/A	ENSP00000384015.1
	SUN1	ENST00000457378.6	TSL:1	c.141-3T>C		splice_region intron	N/A	ENSP00000395952.2
	SUN1	ENST00000405266.5	TSL:5	c.78-3T>C		splice_region intron	N/A	ENSP00000384116.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152246 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00233 AC: 357 AN: 152988 AF XY: 0.00237

Gnomad AFR exome AF: 0.000234

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0302

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000496

Gnomad OTH exome AF: 0.000930

GnomAD4 exome AF: 0.00114 AC: 1580 AN: 1386506 Hom.: 28 Cov.: 30 AF XY: 0.00114 AC XY: 775 AN XY: 681846

African (AFR) AF: 0.0000636 AC: 2 AN: 31438

American (AMR) AF: 0.000117 AC: 4 AN: 34202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24632

East Asian (EAS) AF: 0.0373 AC: 1332 AN: 35740

South Asian (SAS) AF: 0.000800 AC: 62 AN: 77546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49304

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5644

European-Non Finnish (NFE) AF: 0.0000159 AC: 17 AN: 1070386

Other (OTH) AF: 0.00279 AC: 161 AN: 57614

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152364 Hom.: 8 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74506

African (AFR) AF: 0.0000961 AC: 4 AN: 41604

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0376 AC: 195 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Emery-Dreifuss muscular dystrophy (1)
-	-	1	SUN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.38
PhyloP100		0.049
PromoterAI		0.0081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs77466627; hg19: chr7-878432; COSMIC: COSV107434181; COSMIC: COSV107434181;