Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_182961.4(SYNE1):c.2697A>G(p.Arg899Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,614,122 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 36 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.549

Publications

5 publications found

Variant links:

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]

SYNE1 Gene-Disease associations (from GenCC):

autosomal recessive ataxia, Beauce type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
arthrogryposis multiplex congenita 3, myogenic type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Emery-Dreifuss muscular dystrophy 4, autosomal dominant
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive myogenic arthrogryposis multiplex congenita
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SYNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037485063).

BP6

Variant 6-152455916-T-C is Benign according to our data. Variant chr6-152455916-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.549 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000794 (121/152312) while in subpopulation EAS AF = 0.0224 (116/5176). AF 95% confidence interval is 0.0191. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.2697A>G	p.Arg899Arg	synonymous	Exon 23 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.2718A>G	p.Arg906Arg	synonymous	Exon 23 of 146	NP_149062.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.2697A>G	p.Arg899Arg	synonymous	Exon 23 of 146	ENSP00000356224.5
SYNE1	ENST00000423061.6	TSL:1	c.2718A>G	p.Arg906Arg	synonymous	Exon 23 of 146	ENSP00000396024.1
SYNE1	ENST00000495090.6	TSL:1	c.1398A>G	p.Arg466Arg	synonymous	Exon 10 of 12	ENSP00000438508.1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0224

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00179

AC:

449

AN:

251394

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0241

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000978

AC:

1430

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

693

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0345

AC:

1370

AN:

39686

South Asian (SAS)

AF:

0.000162

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111964

Other (OTH)

AF:

0.000646

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000794

AC:

121

AN:

152312

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0224

AC:

116

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000857

Hom.:

Bravo

AF:

0.000895

ExAC

AF:

0.00185

AC:

225

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive ataxia, Beauce type (1)

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

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type (1)

Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.2

(source)

DANN

Benign

0.86

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

PhyloP100

0.55

REVEL

Benign

0.030

Sift4G

Benign

0.58

Vest4

0.075

MVP

0.41

ClinPred

0.024

GERP RS

-1.3

Mutation Taster

=88/12

polymorphism

(source)

Splicing

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

Publications

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rs75817012

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over