rs1554471456

Positions:

• chr6-152331153-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_182961.4(SYNE1):​c.13532C>T​(p.Thr4511Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SYNE1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.13532C>T	p.Thr4511Ile	missense_variant	78/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.13532C>T	p.Thr4511Ile	missense_variant	78/146	1	NM_182961.4	P1
SYNE1	ENST00000423061.6	c.13319C>T	p.Thr4440Ile	missense_variant	77/146	1
SYNE1	ENST00000490135.6	n.878C>T		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0060	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.049	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.62	P;.
Vest4		0.55
MutPred		0.45		Gain of catalytic residue at T4511 (P = 0.0236);.;
MVP		0.42
MPC		0.22
ClinPred		0.41	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.26

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554471456; hg19: chr6-152652288;