NM_017667.4:c.422+36A>G

Variant names:

• chr7-93257500-A-G
• rs722263
• NM_017667.4:c.422+36A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017667.4(VPS50):​c.422+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,177,912 control chromosomes in the GnomAD database, including 120,375 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (26433 hom., cov: 32)
  • Exomes 𝑓: 0.42 (93942 hom.)
• Consequence: VPS50 NM_017667.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS50	NM_017667.4	MANE Select	c.422+36A>G		intron	N/A	NP_060137.2
	VPS50	NM_001257998.2		c.332+36A>G		intron	N/A	NP_001244927.1
	VPS50	NM_024553.3		c.422+36A>G		intron	N/A	NP_078829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS50	ENST00000305866.10	TSL:1 MANE Select	c.422+36A>G		intron	N/A	ENSP00000307666.5
	VPS50	ENST00000251739.9	TSL:1	c.422+36A>G		intron	N/A	ENSP00000251739.5
	VPS50	ENST00000441602.5	TSL:1	n.*195+36A>G		intron	N/A	ENSP00000415809.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 82894 AN: 151624 Hom.: 26370 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.465 AC: 99257 AN: 213326 AF XY: 0.445

Gnomad AFR exome AF: 0.899

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.620

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.417 AC: 427787 AN: 1026170 Hom.: 93942 Cov.: 13 AF XY: 0.412 AC XY: 217443 AN XY: 528396

African (AFR) AF: 0.901 AC: 21013 AN: 23322

American (AMR) AF: 0.558 AC: 18947 AN: 33944

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 8079 AN: 21680

East Asian (EAS) AF: 0.610 AC: 22291 AN: 36568

South Asian (SAS) AF: 0.389 AC: 27229 AN: 69914

European-Finnish (FIN) AF: 0.406 AC: 20912 AN: 51476

Middle Eastern (MID) AF: 0.306 AC: 1470 AN: 4798

European-Non Finnish (NFE) AF: 0.390 AC: 288012 AN: 738990

Other (OTH) AF: 0.436 AC: 19834 AN: 45478

GnomAD4 genome AF: 0.547 AC: 83025 AN: 151742 Hom.: 26433 Cov.: 32 AF XY: 0.546 AC XY: 40461 AN XY: 74142

African (AFR) AF: 0.888 AC: 36831 AN: 41482

American (AMR) AF: 0.528 AC: 8043 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1307 AN: 3468

East Asian (EAS) AF: 0.614 AC: 3162 AN: 5154

South Asian (SAS) AF: 0.401 AC: 1927 AN: 4800

European-Finnish (FIN) AF: 0.403 AC: 4244 AN: 10526

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26019 AN: 67776

Other (OTH) AF: 0.508 AC: 1072 AN: 2110

Alfa AF: 0.419 Hom.: 10515

Bravo AF: 0.573

Asia WGS AF: 0.523 AC: 1812 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.74
DANN	Benign	0.75
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs722263; hg19: chr7-92886812; COSMIC: COSV104381521; COSMIC: COSV104381521;