dbSNP rs3793427: VPS37A:c.1114-26G>C (chr8-17286321-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152415.3(VPS37A):c.1114-26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,594,638 control chromosomes in the GnomAD database, including 89,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 13117 hom., cov: 32)

Exomes 𝑓: 0.31 ( 76447 hom. )

Consequence

VPS37A
NM_152415.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.20

Publications

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

VPS37A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 8-17286321-G-C is Benign according to our data. Variant chr8-17286321-G-C is described in ClinVar as Benign. ClinVar VariationId is 1247255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS37A	NM_152415.3	MANE Select	c.1114-26G>C	intron	N/A	NP_689628.2	Q8NEZ2-1
VPS37A	NM_001363173.2		c.1114-26G>C	intron	N/A	NP_001350102.1	Q8NEZ2-1
VPS37A	NM_001363167.1		c.1096-26G>C	intron	N/A	NP_001350096.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.1114-26G>C	intron	N/A	ENSP00000318629.4	Q8NEZ2-1
VPS37A	ENST00000521829.5	TSL:1	c.1039-26G>C	intron	N/A	ENSP00000429680.1	Q8NEZ2-2
VPS37A	ENST00000967262.1		c.1222-26G>C	intron	N/A	ENSP00000637321.1

Frequencies

GnomAD3 genomes

AF:

0.388

AC:

59022

AN:

151932

Hom.:

13086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.559

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.316

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.394

GnomAD2 exomes

AF:

0.386

AC:

92382

AN:

239030

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.555

Gnomad AMR exome

AF:

0.486

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.705

Gnomad FIN exome

AF:

0.308

Gnomad NFE exome

AF:

0.273

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.305

AC:

440049

AN:

1442588

Hom.:

76447

Cov.:

AF XY:

0.308

AC XY:

221397

AN XY:

718032

show subpopulations

African (AFR)

AF:

0.573

AC:

18791

AN:

32790

American (AMR)

AF:

0.478

AC:

20897

AN:

43760

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

9688

AN:

25890

East Asian (EAS)

AF:

0.745

AC:

29152

AN:

39144

South Asian (SAS)

AF:

0.468

AC:

39693

AN:

84834

European-Finnish (FIN)

AF:

0.305

AC:

16132

AN:

52858

Middle Eastern (MID)

AF:

0.439

AC:

2515

AN:

5724

European-Non Finnish (NFE)

AF:

0.258

AC:

282790

AN:

1098038

Other (OTH)

AF:

0.342

AC:

20391

AN:

59550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

13768

27536

41304

55072

68840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10016

20032

30048

40064

50080

<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:

0.389

AC:

59104

AN:

152050

Hom.:

13117

Cov.:

AF XY:

0.396

AC XY:

29403

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.559

AC:

23186

AN:

41450

American (AMR)

AF:

0.436

AC:

6651

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

1286

AN:

3472

East Asian (EAS)

AF:

0.717

AC:

3701

AN:

5162

South Asian (SAS)

AF:

0.475

AC:

2289

AN:

4824

European-Finnish (FIN)

AF:

0.316

AC:

3336

AN:

10566

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17564

AN:

67986

Other (OTH)

AF:

0.402

AC:

851

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1710

3420

5129

6839

8549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.285

Hom.:

4162

Bravo

AF:

0.408

Asia WGS

AF:

0.599

AC:

2080

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia 53 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over