6-152125352-C-T

Position:

• chr6-152125352-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000427531.6(ESR1):​c.*4C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,549,354 control chromosomes in the GnomAD database, including 32,878 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3100 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29778 hom.)
• Consequence: ESR1 ENST00000427531.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_001347702.2	c.2688-2676G>A		intron_variant		ENST00000354674.5	NP_001334631.1
SYNE1	NM_182961.4	c.26154-2676G>A		intron_variant		ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000354674.5	c.2688-2676G>A		intron_variant		5	NM_001347702.2	ENSP00000346701
SYNE1	ENST00000367255.10	c.26154-2676G>A		intron_variant		1	NM_182961.4	ENSP00000356224	P1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30603 AN: 152042 Hom.: 3103 Cov.: 33

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.189 AC: 28183 AN: 148896 Hom.: 2892 AF XY: 0.183 AC XY: 14670 AN XY: 80210

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.204 AC: 284601 AN: 1397194 Hom.: 29778 Cov.: 32 AF XY: 0.201 AC XY: 138296 AN XY: 689158

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.212

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.201 AC: 30603 AN: 152160 Hom.: 3100 Cov.: 33 AF XY: 0.201 AC XY: 14933 AN XY: 74382

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.193

Alfa AF: 0.201 Hom.: 1652

Bravo AF: 0.196

Asia WGS AF: 0.141 AC: 493 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2813563; hg19: chr6-152446487; COSMIC: COSV54934931;