chr6-152425458-A-T

Variant names:

• chr6-152425458-A-T
• rs111250109
• NM_182961.4:c.5190T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.5190T>A​(p.Asp1730Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,614,108 control chromosomes in the GnomAD database, including 1,838 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (172 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1666 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.22
• Publications: 14 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015822649).
• BP6: Variant 6-152425458-A-T is Benign according to our data. Variant chr6-152425458-A-T is described in ClinVar as Benign. ClinVar VariationId is 130446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

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.5190T>A	p.Asp1730Glu	missense	Exon 39 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.5211T>A	p.Asp1737Glu	missense	Exon 39 of 146	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.5190T>A	p.Asp1730Glu	missense	Exon 39 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.5211T>A	p.Asp1737Glu	missense	Exon 39 of 146	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.5408T>A		non_coding_transcript_exon	Exon 37 of 55

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6798 AN: 152166 Hom.: 170 Cov.: 33

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.0549

GnomAD2 exomes AF: 0.0427 AC: 10739 AN: 251304 AF XY: 0.0437

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0467

GnomAD4 exome AF: 0.0459 AC: 67119 AN: 1461824 Hom.: 1666 Cov.: 31 AF XY: 0.0460 AC XY: 33420 AN XY: 727216

African (AFR) AF: 0.0355 AC: 1187 AN: 33478

American (AMR) AF: 0.0259 AC: 1158 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 1741 AN: 26136

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39694

South Asian (SAS) AF: 0.0360 AC: 3104 AN: 86254

European-Finnish (FIN) AF: 0.0478 AC: 2555 AN: 53414

Middle Eastern (MID) AF: 0.0506 AC: 292 AN: 5768

European-Non Finnish (NFE) AF: 0.0489 AC: 54345 AN: 1111966

Other (OTH) AF: 0.0449 AC: 2712 AN: 60394

GnomAD4 genome AF: 0.0448 AC: 6815 AN: 152284 Hom.: 172 Cov.: 33 AF XY: 0.0440 AC XY: 3275 AN XY: 74464

African (AFR) AF: 0.0346 AC: 1439 AN: 41562

American (AMR) AF: 0.0392 AC: 600 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 231 AN: 3472

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5170

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4828

European-Finnish (FIN) AF: 0.0446 AC: 474 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0551 AC: 3746 AN: 68014

Other (OTH) AF: 0.0539 AC: 114 AN: 2116

Alfa AF: 0.0541 Hom.: 77

Bravo AF: 0.0424

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.0516 AC: 444

ExAC AF: 0.0442 AC: 5363

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0543

EpiControl AF: 0.0527

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0070
DANN	Benign	0.81
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.24	N
PhyloP100		-2.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.041
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.048
MutPred		0.26		Gain of ubiquitination at K1733 (P = 0.1204)
MPC		0.12
ClinPred		0.00058	T
GERP RS		-6.3
Varity_R		0.038
gMVP		0.024
Mutation Taster		=95/5	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs111250109; hg19: chr6-152746593; COSMIC: COSV55083556; COSMIC: COSV55083556;