6-152122333-G-T

Variant names:

• chr6-152122333-G-T
• rs2250122
• NM_182961.4:c.*103C>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.*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
• Publications: 16 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.*103C>A		3_prime_UTR	Exon 146 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.*103C>A		3_prime_UTR	Exon 18 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.*103C>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.*103C>A		3_prime_UTR	Exon 146 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.*103C>A		3_prime_UTR	Exon 18 of 18	ENSP00000346701.4	F8WAI0
	SYNE1	ENST00000423061.6	TSL:1	c.*103C>A		3_prime_UTR	Exon 146 of 146	ENSP00000396024.1	A0A0C4DG40

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

African (AFR) AF: 0.105 AC: 3487 AN: 33102

American (AMR) AF: 0.316 AC: 14068 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6536 AN: 25994

East Asian (EAS) AF: 0.303 AC: 11968 AN: 39558

South Asian (SAS) AF: 0.344 AC: 29266 AN: 85178

European-Finnish (FIN) AF: 0.139 AC: 7259 AN: 52052

Middle Eastern (MID) AF: 0.269 AC: 1154 AN: 4294

European-Non Finnish (NFE) AF: 0.232 AC: 254375 AN: 1097768

Other (OTH) AF: 0.239 AC: 14284 AN: 59686

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

African (AFR) AF: 0.111 AC: 4611 AN: 41532

American (AMR) AF: 0.301 AC: 4604 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3470

East Asian (EAS) AF: 0.312 AC: 1613 AN: 5178

South Asian (SAS) AF: 0.330 AC: 1594 AN: 4824

European-Finnish (FIN) AF: 0.132 AC: 1396 AN: 10604

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15934 AN: 68004

Other (OTH) AF: 0.235 AC: 496 AN: 2112

Alfa AF: 0.231 Hom.: 6096

Bravo AF: 0.214

Asia WGS AF: 0.308 AC: 1067 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	2.7
DANN	Benign	0.63
PhyloP100		0.023
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: rs2250122; hg19: chr6-152443468;