6-152125185-C-T

Variant names:

• chr6-152125185-C-T
• rs2813562
• NM_182961.4:c.26154-2509G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182961.4(SYNE1):​c.26154-2509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,481,630 control chromosomes in the GnomAD database, including 33,522 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 0.23 (4052 hom., cov: 32)
  • Exomes 𝑓: 0.21 (29470 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 6 publications found

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]

ESR1 Gene-Disease associations (from GenCC):

• estrogen resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.26154-2509G>A		intron_variant	Intron 145 of 145	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.2688-2509G>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.26154-2509G>A		intron_variant	Intron 145 of 145	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.2688-2509G>A		intron_variant	Intron 17 of 17	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34637 AN: 151830 Hom.: 4053 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.207 AC: 275078 AN: 1329682 Hom.: 29470 AF XY: 0.204 AC XY: 132596 AN XY: 650836

African (AFR) AF: 0.296 AC: 9054 AN: 30582

American (AMR) AF: 0.199 AC: 6622 AN: 33246

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 3974 AN: 21978

East Asian (EAS) AF: 0.142 AC: 4998 AN: 35164

South Asian (SAS) AF: 0.109 AC: 7505 AN: 68564

European-Finnish (FIN) AF: 0.268 AC: 11588 AN: 43256

Middle Eastern (MID) AF: 0.155 AC: 844 AN: 5444

European-Non Finnish (NFE) AF: 0.212 AC: 219609 AN: 1036314

Other (OTH) AF: 0.197 AC: 10884 AN: 55134

GnomAD4 genome AF: 0.228 AC: 34655 AN: 151948 Hom.: 4052 Cov.: 32 AF XY: 0.226 AC XY: 16786 AN XY: 74274

African (AFR) AF: 0.286 AC: 11847 AN: 41394

American (AMR) AF: 0.198 AC: 3031 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 635 AN: 3464

East Asian (EAS) AF: 0.125 AC: 646 AN: 5176

South Asian (SAS) AF: 0.109 AC: 526 AN: 4824

European-Finnish (FIN) AF: 0.287 AC: 3023 AN: 10522

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

European-Non Finnish (NFE) AF: 0.210 AC: 14306 AN: 67972

Other (OTH) AF: 0.213 AC: 448 AN: 2108

Alfa AF: 0.219 Hom.: 497

Bravo AF: 0.227

Asia WGS AF: 0.149 AC: 519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.55
PhyloP100		-1.4
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: rs2813562; hg19: chr6-152446320; COSMIC: COSV107318899;