1-12244235-TCTC-T

Variant names:

• chr1-12244235-TCTC-T
• rs754935525
• NM_015378.4:c.176-8_176-6delCCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_015378.4(VPS13D):​c.176-8_176-6delCCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,599,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: VPS13D NM_015378.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0800
• Publications: 0 publications found

Genes affected

VPS13D (HGNC:23595): (vacuolar protein sorting 13 homolog D) This gene encodes a protein belonging to the vacuolar-protein-sorting-13 gene family. In yeast, vacuolar-protein-sorting-13 proteins are involved in trafficking of membrane proteins between the trans-Golgi network and the prevacuolar compartment. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode distinct isoforms. [provided by RefSeq, Jul 2008]

VPS13D Gene-Disease associations (from GenCC):

• autosomal recessive cerebellar ataxia-saccadic intrusion syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-12244235-TCTC-T is Benign according to our data. Variant chr1-12244235-TCTC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2893066.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015378.4. 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
	VPS13D	NM_015378.4	MANE Select	c.176-8_176-6delCCT		splice_region intron	N/A	NP_056193.2	Q5THJ4-1
	VPS13D	NM_018156.4		c.176-8_176-6delCCT		splice_region intron	N/A	NP_060626.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13D	ENST00000620676.6	TSL:1 MANE Select	c.176-10_176-8delCTC		splice_region intron	N/A	ENSP00000478104.1	Q5THJ4-1
	VPS13D	ENST00000613099.4	TSL:1	c.176-10_176-8delCTC		splice_region intron	N/A	ENSP00000482233.1	Q5THJ4-2
	VPS13D	ENST00000476169.1	TSL:3	n.-188_-186delCTC		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000210 AC: 5 AN: 238394 AF XY: 0.0000232

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1447624 Hom.: 0 AF XY: 0.0000167 AC XY: 12 AN XY: 719706

African (AFR) AF: 0.000338 AC: 11 AN: 32498

American (AMR) AF: 0.0000491 AC: 2 AN: 40742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107170

Other (OTH) AF: 0.0000838 AC: 5 AN: 59690

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74488

African (AFR) AF: 0.000168 AC: 7 AN: 41586

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs754935525; hg19: chr1-12304292;