chr1-12234322-A-G

Variant names:

• chr1-12234322-A-G
• rs780680462
• NM_015378.4:c.56A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015378.4(VPS13D):​c.56A>G​(p.Asn19Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VPS13D NM_015378.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09036219).

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.56A>G	p.Asn19Ser	missense	Exon 2 of 70	NP_056193.2	Q5THJ4-1
	VPS13D	NM_018156.4		c.56A>G	p.Asn19Ser	missense	Exon 2 of 69	NP_060626.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13D	ENST00000620676.6	TSL:1 MANE Select	c.56A>G	p.Asn19Ser	missense	Exon 2 of 70	ENSP00000478104.1	Q5THJ4-1
	VPS13D	ENST00000613099.4	TSL:1	c.56A>G	p.Asn19Ser	missense	Exon 2 of 69	ENSP00000482233.1	Q5THJ4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251466 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.035	N
PhyloP100		4.7
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.25		Loss of methylation at K16 (P = 0.191)
MVP		0.043
ClinPred		0.91	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.32
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs780680462; hg19: chr1-12294379;