chr6-152121768-CT-C

Variant names:

• chr6-152121768-CT-C
• rs71660056
• ENST00000367251.7:c.*872delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000367251.7(SYNE1):​c.*872delA variant causes a splice region change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.42 (13872 hom., cov: 0)
  • Exomes 𝑓: 0.49 (64 hom.)
• Consequence: SYNE1 ENST00000367251.7 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.270
• Publications: 3 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367251.7. 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.*667delA		3_prime_UTR	Exon 146 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.*667delA		3_prime_UTR	Exon 18 of 18	NP_001334631.1	F8WAI0
	SYNE1	NM_033071.5		c.*667delA		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	ENST00000367251.7	TSL:1	c.*872delA		splice_region	Exon 31 of 31	ENSP00000356220.3	H0Y325
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.*667delA		3_prime_UTR	Exon 146 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.*667delA		3_prime_UTR	Exon 18 of 18	ENSP00000346701.4	F8WAI0

Frequencies

GnomAD3 genomes AF: 0.423 AC: 63464 AN: 150082 Hom.: 13856 Cov.: 0

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.489 AC: 263 AN: 538 Hom.: 64 Cov.: 0 AF XY: 0.469 AC XY: 153 AN XY: 326

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.553 AC: 231 AN: 418

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.279 AC: 29 AN: 104

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.423 AC: 63529 AN: 150188 Hom.: 13872 Cov.: 0 AF XY: 0.421 AC XY: 30922 AN XY: 73376

African (AFR) AF: 0.516 AC: 21164 AN: 41008

American (AMR) AF: 0.320 AC: 4819 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1222 AN: 3430

East Asian (EAS) AF: 0.258 AC: 1319 AN: 5122

South Asian (SAS) AF: 0.286 AC: 1356 AN: 4738

European-Finnish (FIN) AF: 0.559 AC: 5679 AN: 10168

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.398 AC: 26852 AN: 67384

Other (OTH) AF: 0.366 AC: 762 AN: 2080

Alfa AF: 0.304 Hom.: 548

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebellar ataxia (1)
-	1	-	Emery-Dreifuss muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
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: rs71660056; hg19: chr6-152442903; COSMIC: COSV54929090; COSMIC: COSV54929090;