Variant 14-95417888-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152592.6(SYNE3):c.2866G>T(p.Ala956Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000785 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00082 ( 0 hom. )

Consequence

SYNE3
NM_152592.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0490

Variant links:

Genes affected

SYNE3 (HGNC:19861): (spectrin repeat containing nuclear envelope family member 3) Enables actin filament binding activity and cytoskeleton-nuclear membrane anchor activity. Involved in cytoskeleton organization; establishment of protein localization to membrane; and regulation of cell shape. Located in nuclear membrane. Part of meiotic nuclear membrane microtubule tethering complex. Biomarker of Huntington's disease. [provided by Alliance of Genome Resources, Apr 2022]

SYNE3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04295227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE3	NM_152592.6 linkuse as main transcript	c.2866G>T	p.Ala956Ser	missense_variant	18/18	ENST00000682763.1
SYNE3	NM_001363692.2 linkuse as main transcript	c.2851G>T	p.Ala951Ser	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE3	ENST00000682763.1 linkuse as main transcript	c.2866G>T	p.Ala956Ser	missense_variant	18/18		NM_152592.6	P4	Q6ZMZ3-1
SYNE3	ENST00000334258.9 linkuse as main transcript	c.2866G>T	p.Ala956Ser	missense_variant	17/17	1		P4	Q6ZMZ3-1
SYNE3	ENST00000557275.5 linkuse as main transcript	c.2851G>T	p.Ala951Ser	missense_variant	17/17	2		A1	Q6ZMZ3-2
SYNE3	ENST00000554873.5 linkuse as main transcript	c.2137G>T	p.Ala713Ser	missense_variant	13/13	5

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000131

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:

0.000897

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000350

AC:

AN:

251470

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000818

AC:

1196

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

540

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.000467

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000656

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.2866G>T (p.A956S) alteration is located in exon 17 (coding exon 17) of the SYNE3 gene. This alteration results from a G to T substitution at nucleotide position 2866, causing the alanine (A) at amino acid position 956 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

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Benign

0.95

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.055

Sift

Benign

0.79

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.20

B;B;.

Vest4

0.098

MVP

0.20

MPC

0.19

ClinPred

0.033

GERP RS

3.7

Varity_R

0.14

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over