rs567376316

Positions:

• chr6-152122458-G-A
• chr6-152122458-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS2_Supporting

The NM_182961.4(SYNE1):​c.26372C>T​(p.Thr8791Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,162 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (1 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.01

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

SYNE1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04168141).
• BS2: High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.26372C>T	p.Thr8791Met	missense_variant	146/146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.2906C>T	p.Thr969Met	missense_variant	18/18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.26372C>T	p.Thr8791Met	missense_variant	146/146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.2906C>T	p.Thr969Met	missense_variant	18/18	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000252 AC: 63 AN: 249758 Hom.: 1 AF XY: 0.000215 AC XY: 29 AN XY: 135040

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461860 Hom.: 1 Cov.: 31 AF XY: 0.0000481 AC XY: 35 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 8743 of the SYNE1 protein (p.Thr8743Met). This variant is present in population databases (rs567376316, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 502164). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D;.;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.11	T;.;T;T;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.97	D;.;.;.;.
Vest4		0.10
MutPred		0.36		Loss of phosphorylation at T8791 (P = 0.014);.;.;.;.;
MVP		0.40
MPC		0.21
ClinPred		0.21	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs567376316; hg19: chr6-152443593;