6-152121768-CTT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_182961.4(SYNE1):c.*666_*667del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 150,818 control chromosomes in the GnomAD database, including 1,230 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1228 hom., cov: 0)
  • Exomes 𝑓: 0.11 (2 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.36

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 -10 ACMG points.

• BP6: Variant 6-152121768-CTT-C is Benign according to our data. Variant chr6-152121768-CTT-C is described in ClinVar as [Benign]. Clinvar id is 355795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_001347702.2	c.*666_*667del		3_prime_UTR_variant	18/18	ENST00000354674.5
SYNE1	NM_182961.4	c.*666_*667del		3_prime_UTR_variant	146/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000354674.5	c.*666_*667del		3_prime_UTR_variant	18/18	5	NM_001347702.2
SYNE1	ENST00000367255.10	c.*666_*667del		3_prime_UTR_variant	146/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17612 AN: 150178 Hom.: 1229 Cov.: 0

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.109 AC: 58 AN: 534 Hom.: 2 AF XY: 0.127 AC XY: 41 AN XY: 324

Gnomad4 AMR exome AF: 0.00

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.117 AC: 17622 AN: 150284 Hom.: 1228 Cov.: 0 AF XY: 0.121 AC XY: 8922 AN XY: 73442

Gnomad4 AFR AF: 0.0684

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.150

Alfa AF: 0.0540 Hom.: 548

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebellar ataxia Benign:1

Benign, 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;