15-83565138-T-C

Variant names:

• chr15-83565138-T-C
• rs1257749946
• NM_003027.5:c.119T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003027.5(SH3GL3):​c.119T>C​(p.Ile40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,336,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SH3GL3 NM_003027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23314142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3GL3	NM_003027.5	c.119T>C	p.Ile40Thr	missense_variant	Exon 3 of 9	ENST00000427482.7	NP_003018.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3GL3	ENST00000427482.7	c.119T>C	p.Ile40Thr	missense_variant	Exon 3 of 9	1	NM_003027.5	ENSP00000391372.2
SH3GL3	ENST00000492099.1	n.425T>C		non_coding_transcript_exon_variant	Exon 3 of 3	1
SH3GL3	ENST00000563901.5	n.119T>C		non_coding_transcript_exon_variant	Exon 3 of 9	1		ENSP00000456249.1
SH3GL3	ENST00000324537.5	c.143T>C	p.Ile48Thr	missense_variant	Exon 6 of 12	2		ENSP00000320092.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1336352 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 668926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119T>C (p.I40T) alteration is located in exon 3 (coding exon 3) of the SH3GL3 gene. This alteration results from a T to C substitution at nucleotide position 119, causing the isoleucine (I) at amino acid position 40 to be replaced by a threonine (T). 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	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Benign	0.80
DEOGEN2	Benign	0.065	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.079
Sift	Benign	0.57	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.011	B;B
Vest4		0.39
MutPred		0.76		Loss of stability (P = 0.002);.;
MVP		0.77
MPC		1.2
ClinPred		0.75	D
GERP RS		4.1
Varity_R		0.24
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs1257749946; hg19: chr15-84233890;