rs59276128

Variant names:

• chr8-17247226-G-A
• rs59276128
• NM_152415.3:c.-19G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-17247226-G-A
• chr8-17247226-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_152415.3(VPS37A):​c.-19G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,564,494 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (9 hom.)
• Consequence: VPS37A NM_152415.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.62
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 8-17247226-G-A is Benign according to our data. Variant chr8-17247226-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.-19G>A		5_prime_UTR	Exon 1 of 12	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.-19G>A		5_prime_UTR	Exon 1 of 12	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.-19G>A		5_prime_UTR	Exon 1 of 12	NP_001350096.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37A	ENST00000324849.9	TSL:1 MANE Select	c.-19G>A		5_prime_UTR	Exon 1 of 12	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.-19G>A		5_prime_UTR	Exon 1 of 11	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.-19G>A		5_prime_UTR	Exon 1 of 13	ENSP00000637321.1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152116 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000846 AC: 143 AN: 169112 AF XY: 0.000656

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000874

GnomAD4 exome AF: 0.000392 AC: 553 AN: 1412264 Hom.: 9 Cov.: 31 AF XY: 0.000327 AC XY: 228 AN XY: 698052

African (AFR) AF: 0.0134 AC: 430 AN: 32154

American (AMR) AF: 0.00118 AC: 45 AN: 38090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 36696

South Asian (SAS) AF: 0.00 AC: 0 AN: 80196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49374

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5498

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1086466

Other (OTH) AF: 0.00113 AC: 66 AN: 58484

GnomAD4 genome AF: 0.00415 AC: 631 AN: 152230 Hom.: 5 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74428

African (AFR) AF: 0.0137 AC: 570 AN: 41550

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.00521

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		1.6
PromoterAI		-0.065	Neutral
Mutation Taster		=299/1	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: rs59276128; hg19: chr8-17104735;