Genetic Variant VPS50:p.Thr397Thr (chr7-93296765-C-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_017667.4(VPS50):c.1191C>G(p.Thr397Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 1,603,776 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 2 hom. )

Consequence

VPS50
NM_017667.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.461

Publications

0 publications found

Variant links:

Genes affected

VPS50 (HGNC:25956): (VPS50 subunit of EARP/GARPII complex) Enables SNARE binding activity. Acts upstream of or within endocytic recycling. Located in recycling endosome. Part of EARP complex. [provided by Alliance of Genome Resources, Apr 2022]

VPS50 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

VPS50 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.045).

BP6

Variant 7-93296765-C-G is Benign according to our data. Variant chr7-93296765-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3067277.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.461 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017667.4. 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
	VPS50	NM_017667.4	MANE Select	c.1191C>G	p.Thr397Thr	synonymous	Exon 15 of 28	NP_060137.2
	VPS50	NM_001257998.2		c.1101C>G	p.Thr367Thr	synonymous	Exon 16 of 29	NP_001244927.1	Q96JG6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS50	ENST00000305866.10	TSL:1 MANE Select	c.1191C>G	p.Thr397Thr	synonymous	Exon 15 of 28	ENSP00000307666.5	Q96JG6-1
VPS50	ENST00000441602.5	TSL:1	n.*964C>G		non_coding_transcript_exon	Exon 14 of 27	ENSP00000415809.1	F2Z3F0
VPS50	ENST00000471188.5	TSL:1	n.899C>G		non_coding_transcript_exon	Exon 8 of 20

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000437

AC:

105

AN:

240398

AF XY:

0.000497

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000502

Gnomad NFE exome

AF:

0.000596

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000513

AC:

744

AN:

1451584

Hom.:

Cov.:

AF XY:

0.000521

AC XY:

376

AN XY:

722192

show subpopulations

African (AFR)

AF:

0.0000607

AC:

AN:

32970

American (AMR)

AF:

0.0000936

AC:

AN:

42740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39258

South Asian (SAS)

AF:

0.00129

AC:

109

AN:

84626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50532

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.000539

AC:

598

AN:

1109692

Other (OTH)

AF:

0.000449

AC:

AN:

60078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000375

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000373

Hom.:

Bravo

AF:

0.000283

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.5

(source)

DANN

Benign

0.61

PhyloP100

-0.46

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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