14-95439658-C-A

Position:

• chr14-95439658-C-A

Variant summary

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

The NM_152592.6(SYNE3):​c.2200G>T​(p.Ala734Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: SYNE3 NM_152592.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.468

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]

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=0.082644135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE3	NM_152592.6	c.2200G>T	p.Ala734Ser	missense_variant	13/18	ENST00000682763.1
SYNE3	NM_001363692.2	c.2200G>T	p.Ala734Ser	missense_variant	13/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE3	ENST00000682763.1	c.2200G>T	p.Ala734Ser	missense_variant	13/18		NM_152592.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Sep 01, 2021

The c.2200G>T (p.A734S) alteration is located in exon 12 (coding exon 12) of the SYNE3 gene. This alteration results from a G to T substitution at nucleotide position 2200, causing the alanine (A) at amino acid position 734 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	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.4
DANN	Benign	0.64
DEOGEN2	Benign	0.0067	.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.17	B;B;.
Vest4		0.18
MutPred		0.34		Gain of phosphorylation at A734 (P = 0.0135);Gain of phosphorylation at A734 (P = 0.0135);.;
MVP		0.34
MPC		0.15
ClinPred		0.072	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.098

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95905995;