6-152122626-C-A

Variant names:

• chr6-152122626-C-A
• rs2295192
• NM_182961.4:c.26204G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182961.4(SYNE1):​c.26204G>T​(p.Arg8735Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8735Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.0200
• Publications: 9 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022533447).

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.26204G>T	p.Arg8735Leu	missense	Exon 146 of 146	NP_892006.3
	SYNE1	NM_001347702.2	MANE Plus Clinical	c.2738G>T	p.Arg913Leu	missense	Exon 18 of 18	NP_001334631.1
	SYNE1	NM_033071.5		c.26060G>T	p.Arg8687Leu	missense	Exon 146 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.26204G>T	p.Arg8735Leu	missense	Exon 146 of 146	ENSP00000356224.5
	SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.2738G>T	p.Arg913Leu	missense	Exon 18 of 18	ENSP00000346701.4
	SYNE1	ENST00000423061.6	TSL:1	c.26060G>T	p.Arg8687Leu	missense	Exon 146 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251304 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461814 Hom.: 1 Cov.: 33 AF XY: 0.0000729 AC XY: 53 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111972

Other (OTH) AF: 0.000166 AC: 10 AN: 60388

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.0000110 Hom.: 378

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	1	-	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.5
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.020
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.044
Sift	Benign	0.044	D
Sift4G	Benign	0.14	T
Polyphen		0.086	B
Vest4		0.24
MutPred		0.34		Loss of helix (P = 0.0167)
MVP		0.39
MPC		0.17
ClinPred		0.084	T
GERP RS		1.3
Varity_R		0.23
gMVP		0.36
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2295192; hg19: chr6-152443761;