Genetic Variant NM_024667.3:c.559G>A (chr12-122867415-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024667.3(VPS37B):c.559G>A(p.Ala187Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,492,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A187V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000051 ( 0 hom., cov: 13)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

VPS37B
NM_024667.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.284

Publications

2 publications found

Variant links:

Genes affected

VPS37B (HGNC:25754): (VPS37B subunit of ESCRT-I) Enables calcium-dependent protein binding activity. Involved in positive regulation of viral budding via host ESCRT complex. Located in endosome membrane; midbody; and plasma membrane. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

VPS37B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040055424).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024667.3. 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
	VPS37B	NM_024667.3	MANE Select	c.559G>A	p.Ala187Thr	missense	Exon 4 of 4	NP_078943.1	Q9H9H4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS37B	ENST00000267202.7	TSL:1 MANE Select	c.559G>A	p.Ala187Thr	missense	Exon 4 of 4	ENSP00000267202.2	Q9H9H4
VPS37B	ENST00000535765.5	TSL:3	c.553G>A	p.Ala185Thr	missense	Exon 4 of 4	ENSP00000446075.1	F5H4M0
VPS37B	ENST00000852158.1		c.304G>A	p.Ala102Thr	missense	Exon 2 of 2	ENSP00000522217.1

Frequencies

GnomAD3 genomes

AF:

0.0000507

AC:

AN:

59190

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:

0.000426

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000657

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000381

AC:

AN:

235964

AF XY:

0.0000311

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:

0.0000648

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000495

AC:

AN:

1433328

Hom.:

Cov.:

AF XY:

0.0000562

AC XY:

AN XY:

711440

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

32870

American (AMR)

AF:

0.0000234

AC:

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38554

South Asian (SAS)

AF:

0.0000367

AC:

AN:

81822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47796

Middle Eastern (MID)

AF:

0.00114

AC:

AN:

5274

European-Non Finnish (NFE)

AF:

0.0000519

AC:

AN:

1099268

Other (OTH)

AF:

0.0000169

AC:

AN:

59314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000507

AC:

AN:

59180

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

28170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13270

American (AMR)

AF:

0.00

AC:

AN:

4318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1556

East Asian (EAS)

AF:

0.00

AC:

AN:

2912

South Asian (SAS)

AF:

0.000430

AC:

AN:

2328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

102

European-Non Finnish (NFE)

AF:

0.0000658

AC:

AN:

30414

Other (OTH)

AF:

0.00

AC:

AN:

636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Alfa

AF:

0.0000463

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.7

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.024

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.49

M_CAP

Benign

0.027

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.28

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.91

REVEL

Benign

0.042

Sift

Benign

0.49

Sift4G

Benign

0.47

Polyphen

0.0040

Vest4

0.054

MVP

0.13

MPC

0.26

ClinPred

0.025

GERP RS

2.2

Varity_R

0.030

gMVP

0.28

Mutation Taster

=93/7

polymorphism

(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