16-69315835-T-C

Variant names:

• chr16-69315835-T-C
• rs153050
• NM_013245.3:c.22-173T>C

Variant summary

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

The NM_013245.3(VPS4A):​c.22-173T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 151,992 control chromosomes in the GnomAD database, including 33,265 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 0.66 (33265 hom., cov: 31)
• Consequence: VPS4A NM_013245.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.141
• Publications: 14 publications found

Genes affected

VPS4A (HGNC:13488): (vacuolar protein sorting 4 homolog A) The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 16; the gene for the other resides on chromosome 18. [provided by RefSeq, Jul 2008]

VPS4A Gene-Disease associations (from GenCC):

• cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000260914 (HGNC:):

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 = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4A	NM_013245.3	c.22-173T>C		intron_variant	Intron 1 of 10	ENST00000254950.13	NP_037377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS4A	ENST00000254950.13	c.22-173T>C		intron_variant	Intron 1 of 10	1	NM_013245.3	ENSP00000254950.11
ENSG00000260914	ENST00000570054.3	c.94-173T>C		intron_variant	Intron 1 of 9	5		ENSP00000461295.3

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100240 AN: 151874 Hom.: 33233 Cov.: 31

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.657

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.660 AC: 100318 AN: 151992 Hom.: 33265 Cov.: 31 AF XY: 0.660 AC XY: 49010 AN XY: 74308

African (AFR) AF: 0.703 AC: 29143 AN: 41434

American (AMR) AF: 0.641 AC: 9782 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3468

East Asian (EAS) AF: 0.519 AC: 2684 AN: 5174

South Asian (SAS) AF: 0.682 AC: 3291 AN: 4822

European-Finnish (FIN) AF: 0.653 AC: 6904 AN: 10576

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44305 AN: 67938

Other (OTH) AF: 0.661 AC: 1395 AN: 2110

Alfa AF: 0.650 Hom.: 121324

Bravo AF: 0.661

Asia WGS AF: 0.613 AC: 2130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.55
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs153050; hg19: chr16-69349738;