chr8-17280101-A-C

Variant names:

Variant summary

Our verdict is The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_152415.3(VPS37A):c.787A>C (p.Lys263Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000446 (AC=72) in the gnomAD database across 1,612,670 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000147. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

VPS37A
NM_152415.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.92

Publications

2 publications found

Variant links:

Genes affected

VPS37A (HGNC:24928): (VPS37A subunit of ESCRT-I) This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

VPS37A Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 53
Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
complex hereditary spastic paraplegia
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

VPS37A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_152415.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 points.

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000147 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_152415.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS37A	NM_152415.3	MANE Select	c.787A>C	p.Lys263Gln	missense	Exon 7 of 12	NP_689628.2	Q8NEZ2-1
VPS37A	NM_001363173.2		c.787A>C	p.Lys263Gln	missense	Exon 7 of 12	NP_001350102.1	Q8NEZ2-1
VPS37A	NM_001363167.1		c.787A>C	p.Lys263Gln	missense	Exon 7 of 12	NP_001350096.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.787A>C	p.Lys263Gln	missense	Exon 7 of 12	ENSP00000318629.4	Q8NEZ2-1
VPS37A	ENST00000521829.5	TSL:1	c.712A>C	p.Lys238Gln	missense	Exon 6 of 11	ENSP00000429680.1	Q8NEZ2-2
VPS37A	ENST00000967262.1		c.895A>C	p.Lys299Gln	missense	Exon 8 of 13	ENSP00000637321.1	A0ACI8VEW5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00318

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000359

AC:

AN:

250462

AF XY:

0.0000369

show subpopulations

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:

0.0000619

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000459

AC:

AN:

1460620

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000543

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1111380

Other (OTH)

AF:

0.000116

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00318

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.0000567

AC:

AN:

264690

Hom.:

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0000848

AC:

AN:

47188

Hom.:

Local populations

ESP6500 (Exome Variant Server)

AF:

0.0000769

AC:

AN:

13004

show subpopulations

European American

AF:

0.000116

AC:

AN:

8598

African American

AF:

0.00

AC:

AN:

4406

Turkish Variome

AF:

0.00124

AC:

AN:

5164

Hom.:

Case/control cohorts

Cohort

Cases

Controls

BipEx

(Bipolar disorder (including schizoaffective))

0 / 28408AF: 0

2 / 28834AF: 0.0000693626

Epi25

(Epilepsy)

5 / 41938AF: 0.000119224

3 / 66856AF: 0.0000448726

SCHEMA

(Schizophrenia)

7 / 121608AF: 0.0000575620

10 / 190582AF: 0.0000524709

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 53 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.029

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.7

PhyloP100

6.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.51

REVEL

Uncertain

0.39

Sift

Benign

0.057

Sift4G

Benign

0.13

Varity_R

0.34

popEVE

Benign

-2.8

(source)

VESM-3B

Benign

-6.7

(source)

FuncVEP CTI

Benign

0.068

(source)

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-4.5

(source)

GPN-Star score

4.5

(source)

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over