8-17247268-C-T

Variant names:

• chr8-17247268-C-T
• rs146098391
• NM_152415.3:c.24C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_152415.3(VPS37A):​c.24C>T​(p.Thr8Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,570,566 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: VPS37A NM_152415.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.291
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-17247268-C-T is Benign according to our data. Variant chr8-17247268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 696459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.291 with no splicing effect.
• 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.24C>T	p.Thr8Thr	synonymous	Exon 1 of 12	NP_689628.2	Q8NEZ2-1
	VPS37A	NM_001363173.2		c.24C>T	p.Thr8Thr	synonymous	Exon 1 of 12	NP_001350102.1	Q8NEZ2-1
	VPS37A	NM_001363167.1		c.24C>T	p.Thr8Thr	synonymous	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.24C>T	p.Thr8Thr	synonymous	Exon 1 of 12	ENSP00000318629.4	Q8NEZ2-1
	VPS37A	ENST00000521829.5	TSL:1	c.24C>T	p.Thr8Thr	synonymous	Exon 1 of 11	ENSP00000429680.1	Q8NEZ2-2
	VPS37A	ENST00000967262.1		c.24C>T	p.Thr8Thr	synonymous	Exon 1 of 13	ENSP00000637321.1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152102 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

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: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000861 AC: 154 AN: 178910 AF XY: 0.000748

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000964

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.000422

GnomAD4 exome AF: 0.000317 AC: 450 AN: 1418346 Hom.: 2 Cov.: 31 AF XY: 0.000274 AC XY: 192 AN XY: 701532

African (AFR) AF: 0.0111 AC: 358 AN: 32350

American (AMR) AF: 0.000872 AC: 34 AN: 39012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25360

East Asian (EAS) AF: 0.00 AC: 0 AN: 37006

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49810

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5660

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1089790

Other (OTH) AF: 0.000732 AC: 43 AN: 58704

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152220 Hom.: 5 Cov.: 32 AF XY: 0.00374 AC XY: 278 AN XY: 74422

African (AFR) AF: 0.0135 AC: 562 AN: 41524

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00414

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		0.29
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism

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: rs146098391; hg19: chr8-17104777;