3-138460642-A-G

Variant names:

• chr3-138460642-A-G
• NM_031913.5:c.770A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031913.5(ESYT3):​c.770A>G​(p.Asn257Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N257K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ESYT3 NM_031913.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45

Genes affected

ESYT3 (HGNC:24295): (extended synaptotagmin 3) Predicted to enable calcium ion binding activity and phospholipid binding activity. Predicted to be involved in endoplasmic reticulum-plasma membrane tethering and lipid transport. Located in endoplasmic reticulum-plasma membrane contact site. Is extrinsic component of cytoplasmic side of plasma membrane; integral component of plasma membrane; and intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESYT3	NM_031913.5	c.770A>G	p.Asn257Ser	missense_variant	Exon 7 of 23	ENST00000389567.9	NP_114119.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESYT3	ENST00000389567.9	c.770A>G	p.Asn257Ser	missense_variant	Exon 7 of 23	1	NM_031913.5	ENSP00000374218.4
ESYT3	ENST00000289135.4	c.770A>G	p.Asn257Ser	missense_variant	Exon 7 of 8	5		ENSP00000289135.4
ESYT3	ENST00000486831.5	n.983A>G		non_coding_transcript_exon_variant	Exon 7 of 22	5
ESYT3	ENST00000490835.5	n.770A>G		non_coding_transcript_exon_variant	Exon 7 of 18	2		ENSP00000417388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 0.00000180

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

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.770A>G (p.N257S) alteration is located in exon 7 (coding exon 7) of the ESYT3 gene. This alteration results from a A to G substitution at nucleotide position 770, causing the asparagine (N) at amino acid position 257 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	0.0039	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.91	P;.
Vest4		0.88
MutPred		0.52		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.82
MPC		0.23
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.56
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-138179484;