8-99134718-T-A

Variant names:

• chr8-99134718-T-A
• rs77759532
• NM_017890.5:c.1293T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_017890.5(VPS13B):​c.1293T>A​(p.Thr431Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,606,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T431T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.523
• Publications: 1 publications found

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 8-99134718-T-A is Benign according to our data. Variant chr8-99134718-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 706022.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.523 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. 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
	VPS13B	NM_017890.5	MANE Plus Clinical	c.1293T>A	p.Thr431Thr	synonymous	Exon 9 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.1293T>A	p.Thr431Thr	synonymous	Exon 9 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.1293T>A	p.Thr431Thr	synonymous	Exon 9 of 18	NP_056058.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.1293T>A	p.Thr431Thr	synonymous	Exon 9 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.1293T>A	p.Thr431Thr	synonymous	Exon 9 of 62	ENSP00000349685.2
	VPS13B	ENST00000355155.6	TSL:1	n.1293T>A		non_coding_transcript_exon	Exon 9 of 28	ENSP00000347281.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250454 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000894 AC: 13 AN: 1454348 Hom.: 0 Cov.: 30 AF XY: 0.00000829 AC XY: 6 AN XY: 723550

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.00 AC: 0 AN: 84984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1106942

Other (OTH) AF: 0.0000166 AC: 1 AN: 60118

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 9

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cohen syndrome (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.6
DANN	Benign	0.72
PhyloP100		0.52

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: rs77759532; hg19: chr8-100146946;