11-119067895-T-A

Variant names:

• chr11-119067895-T-A
• rs782425373
• NM_021729.6:c.72T>A

Variant summary

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

The NM_021729.6(VPS11):​c.72T>A​(p.Asn24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,596,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N24S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: VPS11 NM_021729.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 0 publications found

Genes affected

VPS11 (HGNC:14583): (VPS11 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps11 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

VPS11-DT (HGNC:55227): (VPS11 divergent transcript)

LOC124902769 (HGNC:):

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=0.08101937).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021729.6. 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
	VPS11	NM_021729.6	MANE Select	c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	NP_068375.3
	VPS11	NM_001378218.1		c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	NP_001365147.1
	VPS11	NM_001378219.1		c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	NP_001365148.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS11	ENST00000621676.5	TSL:1 MANE Select	c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	ENSP00000481126.1	A0A087WXL6
	VPS11	ENST00000952525.1		c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	ENSP00000622584.1
	VPS11	ENST00000863302.1		c.72T>A	p.Asn24Lys	missense	Exon 1 of 16	ENSP00000533361.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

GnomAD2 exomes AF: 0.00000908 AC: 2 AN: 220232 AF XY: 0.00000836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1444148 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716898

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.0000241 AC: 1 AN: 41552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.00 AC: 0 AN: 83586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103510

Other (OTH) AF: 0.00 AC: 0 AN: 59720

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.79
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.081	T
PhyloP100		-0.078
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.92	T
Vest4		0.13
MVP		0.67
GERP RS		-2.0
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16
Mutation Taster		=89/11	polymorphism

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: rs782425373; hg19: chr11-118938606;