16-67184948-C-T

Position:

• chr16-67184948-C-T

Variant summary

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

The NM_178516.4(EXOC3L1):​c.1859G>A​(p.Arg620His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: EXOC3L1 NM_178516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOC3L1	NM_178516.4	c.1859G>A	p.Arg620His	missense_variant	12/14	ENST00000314586.11	NP_848611.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOC3L1	ENST00000314586.11	c.1859G>A	p.Arg620His	missense_variant	12/14	2	NM_178516.4	ENSP00000325674.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000837 AC: 2 AN: 238914 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458762 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725696

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: 0.00000990

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

Nov 08, 2024

The c.1859G>A (p.R620H) alteration is located in exon 12 (coding exon 11) of the EXOC3L1 gene. This alteration results from a G to A substitution at nucleotide position 1859, causing the arginine (R) at amino acid position 620 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	Benign	0.17
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.35
MutPred		0.62		Loss of MoRF binding (P = 0.078);.;.;
MVP		0.72
MPC		2.2
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.46
gMVP		0.36

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: rs1298134728; hg19: chr16-67218851;