6-152121853-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182961.4(SYNE1):c.*583A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 154,136 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (75 hom., cov: 33)
  • Exomes 𝑓: 0.030 (3 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.16

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-152121853-T-C is Benign according to our data. Variant chr6-152121853-T-C is described in ClinVar as [Benign]. Clinvar id is 355796.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_001347702.2	c.*583A>G		3_prime_UTR_variant	18/18	ENST00000354674.5
SYNE1	NM_182961.4	c.*583A>G		3_prime_UTR_variant	146/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000354674.5	c.*583A>G		3_prime_UTR_variant	18/18	5	NM_001347702.2
SYNE1	ENST00000367255.10	c.*583A>G		3_prime_UTR_variant	146/146	1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3636 AN: 151894 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.00472

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0623

Gnomad SAS AF: 0.0604

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0301 AC: 64 AN: 2124 Hom.: 3 Cov.: 0 AF XY: 0.0281 AC XY: 31 AN XY: 1102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00943

Gnomad4 FIN exome AF: 0.0721

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0239 AC: 3637 AN: 152012 Hom.: 75 Cov.: 33 AF XY: 0.0262 AC XY: 1946 AN XY: 74312

Gnomad4 AFR AF: 0.00470

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.0618

Gnomad4 SAS AF: 0.0609

Gnomad4 FIN AF: 0.0622

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0264 Hom.: 18

Bravo AF: 0.0195

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive ataxia, Beauce type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	11
Dann	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3756933; hg19: chr6-152442988;