6-152121768-CT-C

Position:

• chr6-152121768-CT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_182961.4(SYNE1):​c.*667del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.42 (13872 hom., cov: 0)
  • Exomes 𝑓: 0.49 (64 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.270

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_001347702.2	c.*667del		3_prime_UTR_variant	18/18	ENST00000354674.5	NP_001334631.1
SYNE1	NM_182961.4	c.*667del		3_prime_UTR_variant	146/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000354674.5	c.*667del		3_prime_UTR_variant	18/18	5	NM_001347702.2	ENSP00000346701
SYNE1	ENST00000367255.10	c.*667del		3_prime_UTR_variant	146/146	1	NM_182961.4	ENSP00000356224	P1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 63464 AN: 150082 Hom.: 13856 Cov.: 0

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.489 AC: 263 AN: 538 Hom.: 64 Cov.: 0 AF XY: 0.469 AC XY: 153 AN XY: 326

Gnomad4 AMR exome AF: 0.167

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.553

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.423 AC: 63529 AN: 150188 Hom.: 13872 Cov.: 0 AF XY: 0.421 AC XY: 30922 AN XY: 73376

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.366

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebellar ataxia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71660056; hg19: chr6-152442903;