NM_001128159.3:c.2472C>T

Variant names:

• chr17-519155-G-A
• rs376440772
• NM_001128159.3:c.2472C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_001128159.3(VPS53):​c.2472C>T​(p.Leu824Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,539,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: VPS53 NM_001128159.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.31
• Publications: 0 publications found

Genes affected

VPS53 (HGNC:25608): (VPS53 subunit of GARP complex) Involved in endocytic recycling and retrograde transport, endosome to Golgi. Acts upstream of or within lysosomal transport. Located in several cellular components, including Golgi apparatus; perinuclear region of cytoplasm; and recycling endosome. Part of EARP complex and GARP complex. Implicated in pontocerebellar hypoplasia type 2E. [provided by Alliance of Genome Resources, Apr 2022]

VPS53 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive cerebello-cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-519155-G-A is Benign according to our data. Variant chr17-519155-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 724402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000207 (287/1386858) while in subpopulation AMR AF = 0.00102 (33/32378). AF 95% confidence interval is 0.000745. There are 1 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128159.3. 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
	VPS53	NM_001128159.3	MANE Select	c.2472C>T	p.Leu824Leu	synonymous	Exon 22 of 22	NP_001121631.1	Q5VIR6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000437048.7	TSL:1 MANE Select	c.2472C>T	p.Leu824Leu	synonymous	Exon 22 of 22	ENSP00000401435.2	Q5VIR6-4
	VPS53	ENST00000541903.7	TSL:1	n.458C>T		non_coding_transcript_exon	Exon 4 of 4
	VPS53	ENST00000681510.1		c.2322C>T	p.Leu774Leu	synonymous	Exon 19 of 19	ENSP00000505594.1	A0A7P0T9B2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000257 AC: 37 AN: 144126 AF XY: 0.000182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000207 AC: 287 AN: 1386858 Hom.: 1 Cov.: 30 AF XY: 0.000203 AC XY: 139 AN XY: 683792

African (AFR) AF: 0.0000325 AC: 1 AN: 30800

American (AMR) AF: 0.00102 AC: 33 AN: 32378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24476

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 77680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49014

Middle Eastern (MID) AF: 0.000356 AC: 2 AN: 5622

European-Non Finnish (NFE) AF: 0.000222 AC: 238 AN: 1074036

Other (OTH) AF: 0.000209 AC: 12 AN: 57376

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.000393 AC: 6 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.000166

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	VPS53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.097
DANN	Benign	0.80
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs376440772; hg19: chr17-422395;