14-103102540-T-A

Variant summary

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

The NM_001077594.2(EXOC3L4):c.817T>A(p.Ser273Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: EXOC3L4 NM_001077594.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.55

Genes affected

EXOC3L4 (HGNC:20120): (exocyst complex component 3 like 4) Predicted to enable SNARE binding activity. Predicted to be involved in exocyst localization and exocytosis. Predicted to be part of exocyst. [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=0.12104416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC3L4	NM_001077594.2	c.817T>A	p.Ser273Thr	missense_variant	3/12	ENST00000688303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC3L4	ENST00000688303.1	c.817T>A	p.Ser273Thr	missense_variant	3/12		NM_001077594.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.817T>A (p.S273T) alteration is located in exon 2 (coding exon 2) of the EXOC3L4 gene. This alteration results from a T to A substitution at nucleotide position 817, causing the serine (S) at amino acid position 273 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	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	2.3
Dann	Benign	0.69
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.078
Sift	Benign	0.55	T
Sift4G	Benign	0.35	T
Polyphen		0.90	P
Vest4		0.11
MutPred		0.42		Loss of glycosylation at S273 (P = 0.0374);
MVP		0.030
MPC		1.5
ClinPred		0.23	T
GERP RS		-7.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.068
gMVP		0.29

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: rs1161131288; hg19: chr14-103568877;