chr14-95417888-C-A

Position:

• chr14-95417888-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490

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 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	c.2866G>T	p.Ala956Ser	missense_variant	18/18	ENST00000682763.1
SYNE3	NM_001363692.2	c.2851G>T	p.Ala951Ser	missense_variant	18/18

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152184 Hom.: 0 Cov.: 33

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: 88 AN: 251470 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135906

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.: 0 Cov.: 30 AF XY: 0.000743 AC XY: 540 AN XY: 727246

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: 71 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74336

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.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000872

EpiControl AF: 0.000771

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

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	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0054	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs150752116; hg19: chr14-95884225;