7-838795-T-C

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.78-3T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001835
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0490

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 (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 id is 461668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN1	NM_001130965.3	c.78-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000401592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN1	ENST00000401592.6	c.78-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130965.3	P3

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

GnomAD3 exomes AF: 0.00233 AC: 357 AN: 152988 Hom.: 5 AF XY: 0.00237 AC XY: 190 AN XY: 80300

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 SAS exome AF: 0.000713

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

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.000117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0373

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000159

Gnomad4 OTH exome AF: 0.00279

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

Gnomad4 AFR AF: 0.0000961

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0376

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: 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

Dec 24, 2023

- -

SUN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

This variant is classified as 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_noAF	Benign	-0.81
Cadd	Benign	4.0
Dann	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs77466627; hg19: chr7-878432;