16-67186609-G-T

Variant summary

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

The NM_178516.4(EXOC3L1):c.1333C>A(p.Gln445Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,806 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXOC3L1 NM_178516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

Genes affected

EXOC3L1 (HGNC:27540): (exocyst complex component 3 like 1) Predicted to enable SNARE binding activity. Predicted to be involved in exocyst localization; exocytosis; and peptide hormone secretion. Predicted to be located in secretory granule. 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=0.21942672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC3L1	NM_178516.4	c.1333C>A	p.Gln445Lys	missense_variant	8/14	ENST00000314586.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC3L1	ENST00000314586.11	c.1333C>A	p.Gln445Lys	missense_variant	8/14	2	NM_178516.4	P1
EXOC3L1	ENST00000563889.1	c.1039C>A	p.Gln347Lys	missense_variant	7/12	2
EXOC3L1	ENST00000545725.6	c.1024C>A	p.Gln342Lys	missense_variant	7/12	2
EXOC3L1	ENST00000564324.5	c.*257C>A		3_prime_UTR_variant, NMD_transcript_variant	5/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 06, 2023

The c.1333C>A (p.Q445K) alteration is located in exon 8 (coding exon 7) of the EXOC3L1 gene. This alteration results from a C to A substitution at nucleotide position 1333, causing the glutamine (Q) at amino acid position 445 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Benign	0.62
DEOGEN2	Benign	0.0015	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.84	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.33	N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T
Sift4G	Uncertain	0.039	D;.;D
Polyphen		0.45	P;P;.
Vest4		0.39
MutPred		0.64		Gain of ubiquitination at Q445 (P = 0.0162);.;.;
MVP		0.42
MPC		0.14
ClinPred		0.77	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr16-67220512;