chr3-138455201-C-G

Variant names:

• chr3-138455201-C-G
• rs570708059
• NM_031913.5:c.377C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031913.5(ESYT3):​c.377C>G​(p.Ser126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S126F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ESYT3 NM_031913.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09433505).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031913.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESYT3	NM_031913.5	MANE Select	c.377C>G	p.Ser126Cys	missense	Exon 3 of 23	NP_114119.2	A0FGR9-1
	ESYT3	NM_001322831.2		c.377C>G	p.Ser126Cys	missense	Exon 3 of 24	NP_001309760.1	A0FGR9-1
	ESYT3	NM_001322834.2		c.377C>G	p.Ser126Cys	missense	Exon 3 of 23	NP_001309763.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESYT3	ENST00000389567.9	TSL:1 MANE Select	c.377C>G	p.Ser126Cys	missense	Exon 3 of 23	ENSP00000374218.4	A0FGR9-1
	ESYT3	ENST00000942989.1		c.377C>G	p.Ser126Cys	missense	Exon 3 of 23	ENSP00000613048.1
	ESYT3	ENST00000942987.1		c.377C>G	p.Ser126Cys	missense	Exon 3 of 23	ENSP00000613046.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.058
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.040
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.049	D
Polyphen		0.51	P
Vest4		0.17
MVP		0.23
MPC		0.14
ClinPred		0.84	D
GERP RS		3.2
Varity_R		0.12
gMVP		0.31
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs570708059; hg19: chr3-138174043;