6-152125352-C-T

Variant names:

• chr6-152125352-C-T
• rs2813563
• ENST00000427531.6:c.*4C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.26154-2676G>A		intron_variant	Intron 145 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.2688-2676G>A		intron_variant	Intron 17 of 17	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.26154-2676G>A		intron_variant	Intron 145 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.2688-2676G>A		intron_variant	Intron 17 of 17	5	NM_001347702.2	ENSP00000346701.4

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

GnomAD2 exomes AF: 0.189 AC: 28183 AN: 148896 AF XY: 0.183

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 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

African (AFR) AF: 0.191 AC: 6034 AN: 31586

American (AMR) AF: 0.196 AC: 6988 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4559 AN: 25128

East Asian (EAS) AF: 0.142 AC: 5078 AN: 35732

South Asian (SAS) AF: 0.110 AC: 8691 AN: 79144

European-Finnish (FIN) AF: 0.269 AC: 12926 AN: 48016

Middle Eastern (MID) AF: 0.149 AC: 848 AN: 5686

European-Non Finnish (NFE) AF: 0.212 AC: 228405 AN: 1078296

Other (OTH) AF: 0.191 AC: 11072 AN: 57934

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

African (AFR) AF: 0.190 AC: 7894 AN: 41506

American (AMR) AF: 0.189 AC: 2890 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 636 AN: 3468

East Asian (EAS) AF: 0.126 AC: 653 AN: 5182

South Asian (SAS) AF: 0.109 AC: 527 AN: 4826

European-Finnish (FIN) AF: 0.291 AC: 3072 AN: 10572

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14331 AN: 67996

Other (OTH) AF: 0.193 AC: 409 AN: 2114

Alfa AF: 0.201 Hom.: 1669

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
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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