8-17280101-A-C

Variant names:

• chr8-17280101-A-C
• rs199781923
• NM_152415.3:c.787A>C
• VPS37A p.Lys263Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_152415.3(VPS37A):c.787A>C (p.Lys263Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000446 (AC=72) in the gnomAD database across 1,612,670 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000147. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: VPS37A NM_152415.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.92
• Publications: 2 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]

VPS37A Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 53

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• complex hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000147 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_152415.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VPS37A NM_152415.3	MANE Select	c.787A>C p.Lys263Gln	missense	Exon 7 of 12	Prot: NP_689628.2 UniProt:
	VPS37A NM_001363173.2		c.787A>C p.Lys263Gln	missense	Exon 7 of 12	Prot: NP_001350102.1 UniProt:
	VPS37A NM_001363167.1		c.787A>C p.Lys263Gln	missense	Exon 7 of 12	Prot: NP_001350096.1

VPS37A NM_152415.3

MANE Select

HGVSc / HGVSpc.787A>Cp.Lys263Gln

Exon rankExon 7 of 12

missense

Prot: NP_689628.2UniProt: Q8NEZ2-1

VPS37A NM_001363173.2

HGVSc / HGVSpc.787A>Cp.Lys263Gln

Exon rankExon 7 of 12

missense

Prot: NP_001350102.1UniProt: Q8NEZ2-1

VPS37A NM_001363167.1

HGVSc / HGVSpc.787A>Cp.Lys263Gln

Exon rankExon 7 of 12

missense

Prot: NP_001350096.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VPS37A ENST00000324849.9	TSL:1MANE Select	c.787A>C p.Lys263Gln	missense	Exon 7 of 12	Prot: ENSP00000318629.4 UniProt:
	VPS37A ENST00000521829.5	TSL:1	c.712A>C p.Lys238Gln	missense	Exon 6 of 11	Prot: ENSP00000429680.1 UniProt:
	VPS37A ENST00000967262.1		c.895A>C p.Lys299Gln	missense	Exon 8 of 13	Prot: ENSP00000637321.1 UniProt:

VPS37A ENST00000324849.9

TSL:1MANE Select

HGVSc / HGVSpc.787A>Cp.Lys263Gln

Exon rankExon 7 of 12

missense

Prot: ENSP00000318629.4UniProt: Q8NEZ2-1

VPS37A ENST00000521829.5

TSL:1

HGVSc / HGVSpc.712A>Cp.Lys238Gln

Exon rankExon 6 of 11

missense

Prot: ENSP00000429680.1UniProt: Q8NEZ2-2

VPS37A ENST00000967262.1

HGVSc / HGVSpc.895A>Cp.Lys299Gln

Exon rankExon 8 of 13

missense

Prot: ENSP00000637321.1UniProt: A0ACI8VEW5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152050	Cov:32
GnomAD2 exomes	AF: 0.0000359	AC:9	Hom:	AN:250462	Cov:
GnomAD4 exome	AF: 0.0000459	AC:67	Hom:0	AN:1460620	Cov:30
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152050	Cov:32
TOPMed (Bravo)	AF: 0.0000567	AC:15	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000848	AC:4	Hom:0	AN:47188	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13004	Cov:
Turkish Variome	AF: 0.00124	AC:6	Hom:0	AN:5164	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28408	0.0000694	2	28834
Epi25(Epilepsy)	0.000119	5	41938	0.0000449	3	66856
SCHEMA(Schizophrenia)	0.0000576	7	121608	0.0000525	10	190582

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.068
GPN-Star LLR	N/A	-4.5
GPN-Star score	N/A	4.5
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.50	T
Mutation Taster	N/A	47/53	disease causing
MutationAssessor	Benign	1.7	L
PhyloP100	Uncertain	6.9
popEVE	Benign	-2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.39
Sift	Benign	0.057	T
Sift4G	Benign	0.13	T
Varity_R	N/A	0.34
VESM-3B	Benign	-6.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs199781923;

hg19: chr8-17137610;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar