NM_152415.3:c.125+15C>A

Variant names:

• chr8-17247384-C-A
• rs1318782590
• NM_152415.3:c.125+15C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152415.3(VPS37A):​c.125+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VPS37A NM_152415.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

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]

CNOT7 (HGNC:14101): (CCR4-NOT transcription complex subunit 7) The protein encoded by this gene binds to an anti-proliferative protein, B-cell translocation protein 1, which negatively regulates cell proliferation. Binding of the two proteins, which is driven by phosphorylation of the anti-proliferative protein, causes signaling events in cell division that lead to changes in cell proliferation associated with cell-cell contact. The encoded protein downregulates the innate immune response and therefore provides a therapeutic target for enhancing its antimicrobial activity against foreign agents. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and X. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	NM_152415.3	MANE Select	c.125+15C>A		intron	N/A	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.125+15C>A		intron	N/A	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.125+15C>A		intron	N/A	NP_001350096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.125+15C>A		intron	N/A	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.125+15C>A		intron	N/A	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.125+15C>A		intron	N/A	ENSP00000637321.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384478 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 682734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30956

American (AMR) AF: 0.0000302 AC: 1 AN: 33104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24510

East Asian (EAS) AF: 0.00 AC: 0 AN: 35598

South Asian (SAS) AF: 0.00 AC: 0 AN: 78076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075578

Other (OTH) AF: 0.00 AC: 0 AN: 57308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		1.9
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1318782590; hg19: chr8-17104893;