6-152122254-C-T

Variant names:

• chr6-152122254-C-T
• rs12681
• NM_182961.4:c.*182G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.*182G>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 0.205 in 873,974 control chromosomes in the GnomAD database, including 19,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4258 hom., cov: 33)
  • Exomes 𝑓: 0.20 (14987 hom.)
• Consequence: SYNE1 NM_182961.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.129
• Publications: 17 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-152122254-C-T is Benign according to our data. Variant chr6-152122254-C-T is described in ClinVar as Benign. ClinVar VariationId is 355803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.*182G>A		3_prime_UTR	Exon 146 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.*182G>A		3_prime_UTR	Exon 18 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.*182G>A		3_prime_UTR	Exon 146 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.*182G>A		3_prime_UTR	Exon 146 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.*182G>A		3_prime_UTR	Exon 18 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.*182G>A		3_prime_UTR	Exon 146 of 146	ENSP00000396024.1	A0A0C4DG40

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35269 AN: 152044 Hom.: 4258 Cov.: 33

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.199 AC: 143496 AN: 721814 Hom.: 14987 Cov.: 10 AF XY: 0.194 AC XY: 72182 AN XY: 371612

African (AFR) AF: 0.301 AC: 5612 AN: 18628

American (AMR) AF: 0.201 AC: 6105 AN: 30306

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 3181 AN: 17352

East Asian (EAS) AF: 0.142 AC: 4727 AN: 33260

South Asian (SAS) AF: 0.110 AC: 6291 AN: 57368

European-Finnish (FIN) AF: 0.265 AC: 9391 AN: 35418

Middle Eastern (MID) AF: 0.153 AC: 396 AN: 2588

European-Non Finnish (NFE) AF: 0.205 AC: 100828 AN: 491756

Other (OTH) AF: 0.198 AC: 6965 AN: 35138

GnomAD4 genome AF: 0.232 AC: 35288 AN: 152160 Hom.: 4258 Cov.: 33 AF XY: 0.230 AC XY: 17125 AN XY: 74402

African (AFR) AF: 0.298 AC: 12385 AN: 41494

American (AMR) AF: 0.200 AC: 3056 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.125 AC: 645 AN: 5172

South Asian (SAS) AF: 0.109 AC: 525 AN: 4818

European-Finnish (FIN) AF: 0.292 AC: 3086 AN: 10586

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14308 AN: 68002

Other (OTH) AF: 0.214 AC: 451 AN: 2108

Alfa AF: 0.206 Hom.: 4372

Bravo AF: 0.231

Asia WGS AF: 0.150 AC: 523 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.53
PhyloP100		0.13
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: rs12681; hg19: chr6-152443389; COSMIC: COSV107318897; COSMIC: COSV107318897;