7-93297244-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP3_Moderate

The NM_017667.4(VPS50):c.1361+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS50 NM_017667.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

Genes affected

VPS50 (HGNC:25956): (VPS50 subunit of EARP/GARPII complex) Enables SNARE binding activity. Acts upstream of or within endocytic recycling. Located in recycling endosome. Part of EARP complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.033851467 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 37, new splice context is: tagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.345

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS50	NM_017667.4	c.1361+1G>T		splice_donor_variant		ENST00000305866.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS50	ENST00000305866.10	c.1361+1G>T		splice_donor_variant		1	NM_017667.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388218 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2023

Variant summary: CCDC132 c.1361+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material in a gene where molecular mechanism is uncertain. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonicala 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 190874 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1361+1G>T in individuals affected with Neurodevelopmental Disorder With Microcephaly, Seizures, And Neonatal Cholestasis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: 36
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-92926556;