chr15-83618106-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003027.5(SH3GL3):​c.863C>A​(p.Pro288His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SH3GL3
NM_003027.5 missense

Scores

11
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13
Variant links:
Genes affected
SH3GL3 (HGNC:10832): (SH3 domain containing GRB2 like 3, endophilin A3) Enables identical protein binding activity. Predicted to be involved in synaptic vesicle uncoating. Predicted to be located in acrosomal vesicle; early endosome membrane; and presynapse. Predicted to be part of early endosome. Predicted to be active in glutamatergic synapse; postsynaptic density, intracellular component; and postsynaptic endosome. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH3GL3NM_003027.5 linkc.863C>A p.Pro288His missense_variant Exon 9 of 9 ENST00000427482.7 NP_003018.3 Q99963-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH3GL3ENST00000427482.7 linkc.863C>A p.Pro288His missense_variant Exon 9 of 9 1 NM_003027.5 ENSP00000391372.2 Q99963-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.863C>A (p.P288H) alteration is located in exon 9 (coding exon 9) of the SH3GL3 gene. This alteration results from a C to A substitution at nucleotide position 863, causing the proline (P) at amino acid position 288 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Benign
-0.70
T
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-8.3
D;D
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.76
MutPred
0.60
Loss of disorder (P = 0.0538);.;
MVP
0.78
MPC
1.4
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.90
gMVP
0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-84286858; COSMIC: COSV61054890; API