chr6-152122333-G-T

Position:

• chr6-152122333-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.*103C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,594,380 control chromosomes in the GnomAD database, including 45,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3613 hom., cov: 33)
  • Exomes 𝑓: 0.24 (42147 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0230

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-152122333-G-T is Benign according to our data. Variant chr6-152122333-G-T is described in ClinVar as [Benign]. Clinvar id is 355804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_001347702.2	c.*103C>A		3_prime_UTR_variant	18/18	ENST00000354674.5	NP_001334631.1
SYNE1	NM_182961.4	c.*103C>A		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.*103C>A		3_prime_UTR_variant	18/18	5	NM_001347702.2	ENSP00000346701
SYNE1	ENST00000367255.10	c.*103C>A		3_prime_UTR_variant	146/146	1	NM_182961.4	ENSP00000356224	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31446 AN: 152110 Hom.: 3615 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.237 AC: 342397 AN: 1442152 Hom.: 42147 Cov.: 28 AF XY: 0.241 AC XY: 172753 AN XY: 717658

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.207 AC: 31461 AN: 152228 Hom.: 3613 Cov.: 33 AF XY: 0.208 AC XY: 15518 AN XY: 74442

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.235

Alfa AF: 0.233 Hom.: 4204

Bravo AF: 0.214

Asia WGS AF: 0.308 AC: 1067 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

- -

Autosomal recessive ataxia, Beauce type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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	-0.80
CADD	Benign	2.7
DANN	Benign	0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2250122; hg19: chr6-152443468;