6-152135141-T-G

Variant names:

• chr6-152135141-T-G
• rs41291047
• NM_182961.4:c.25751A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_182961.4(SYNE1):​c.25751A>C​(p.Asp8584Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D8584N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2 O:1
• Conservation: PhyloP100: 8.02
• Publications: 5 publications found

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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000300811 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41885594).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.25751A>C	p.Asp8584Ala	missense	Exon 142 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2285A>C	p.Asp762Ala	missense	Exon 14 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.25607A>C	p.Asp8536Ala	missense	Exon 142 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.25751A>C	p.Asp8584Ala	missense	Exon 142 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2285A>C	p.Asp762Ala	missense	Exon 14 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.25607A>C	p.Asp8536Ala	missense	Exon 142 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000545 AC: 137 AN: 251444 AF XY: 0.000567

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000923

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000611 AC: 893 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.000605 AC XY: 440 AN XY: 727214

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86256

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000728 AC: 809 AN: 1111990

Other (OTH) AF: 0.000414 AC: 25 AN: 60392

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74494

African (AFR) AF: 0.000144 AC: 6 AN: 41580

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000970 Hom.: 3

Bravo AF: 0.000374

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	1	not provided (8)
-	2	-	Autosomal recessive ataxia, Beauce type (2)
-	1	-	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	-	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.78
MVP		0.74
MPC		0.66
ClinPred		0.22	T
GERP RS		6.2
Varity_R		0.58
gMVP		0.44
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41291047; hg19: chr6-152456276;