NM_016075.4:c.812G>A

Variant names:

• chr13-52423602-C-T
• NM_016075.4:c.812G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016075.4(VPS36):​c.812G>A​(p.Cys271Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS36 NM_016075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

Genes affected

VPS36 (HGNC:20312): (vacuolar protein sorting 36 homolog) This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A similar protein complex in rat is associated with RNA polymerase elongation factor II. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016075.4. 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
	VPS36	NM_016075.4	MANE Select	c.812G>A	p.Cys271Tyr	missense	Exon 10 of 14	NP_057159.2	Q86VN1-1
	VPS36	NM_001282168.2		c.785G>A	p.Cys262Tyr	missense	Exon 10 of 14	NP_001269097.1
	VPS36	NM_001282169.2		c.638G>A	p.Cys213Tyr	missense	Exon 10 of 14	NP_001269098.1	Q86VN1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS36	ENST00000378060.9	TSL:1 MANE Select	c.812G>A	p.Cys271Tyr	missense	Exon 10 of 14	ENSP00000367299.3	Q86VN1-1
	VPS36	ENST00000611132.4	TSL:1	c.638G>A	p.Cys213Tyr	missense	Exon 10 of 14	ENSP00000484968.1	Q86VN1-2
	VPS36	ENST00000888388.1		c.812G>A	p.Cys271Tyr	missense	Exon 10 of 14	ENSP00000558447.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.5	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.76		Gain of catalytic residue at C271 (P = 0.0288)
MVP		0.72
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88
Mutation Taster		=4/96	disease causing

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

hg19: chr13-52997737;