NM_152415.3:c.125+41T>G

Variant names:

• chr8-17247410-T-G
• rs1270448786
• NM_152415.3:c.125+41T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_152415.3(VPS37A):​c.125+41T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (0 hom., cov: 0)
  • Exomes 𝑓: 0.12 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS37A NM_152415.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.530
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-17247410-T-G is Benign according to our data. Variant chr8-17247410-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1205684.Status of the report is criteria_provided_single_submitter, 1 stars.

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+41T>G		intron	N/A	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.125+41T>G		intron	N/A	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.125+41T>G		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+41T>G		intron	N/A	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.125+41T>G		intron	N/A	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.125+41T>G		intron	N/A	ENSP00000637321.1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 225 AN: 5868 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0417

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0625

GnomAD2 exomes AF: 0.0278 AC: 649 AN: 23352 AF XY: 0.0234

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.0675

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0404

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.116 AC: 5928 AN: 50900 Hom.: 0 Cov.: 0 AF XY: 0.113 AC XY: 3366 AN XY: 29800

African (AFR) AF: 0.126 AC: 74 AN: 588

American (AMR) AF: 0.160 AC: 293 AN: 1830

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 98 AN: 2146

East Asian (EAS) AF: 0.0647 AC: 76 AN: 1174

South Asian (SAS) AF: 0.110 AC: 1315 AN: 11922

European-Finnish (FIN) AF: 0.0697 AC: 348 AN: 4994

Middle Eastern (MID) AF: 0.144 AC: 21 AN: 146

European-Non Finnish (NFE) AF: 0.131 AC: 3431 AN: 26138

Other (OTH) AF: 0.139 AC: 272 AN: 1962

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0382 AC: 225 AN: 5896 Hom.: 0 Cov.: 0 AF XY: 0.0318 AC XY: 102 AN XY: 3208

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

African (AFR) AF: 0.0531 AC: 64 AN: 1206

American (AMR) AF: 0.0287 AC: 15 AN: 522

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 5 AN: 144

East Asian (EAS) AF: 0.00 AC: 0 AN: 352

South Asian (SAS) AF: 0.0412 AC: 7 AN: 170

European-Finnish (FIN) AF: 0.0116 AC: 3 AN: 258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 16

European-Non Finnish (NFE) AF: 0.0402 AC: 125 AN: 3108

Other (OTH) AF: 0.0588 AC: 6 AN: 102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000613 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.66
PhyloP100		0.53
PromoterAI		0.068	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1270448786; hg19: chr8-17104919;