rs60530833

Positions:

• chr15-99105901-A-AG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_145728.3(SYNM):​c.703dup​(p.Glu235GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYNM NM_145728.3 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.51

Genes affected

SYNM (HGNC:24466): (synemin) The protein encoded by this gene is an intermediate filament (IF) family member. IF proteins are cytoskeletal proteins that confer resistance to mechanical stress and are encoded by a dispersed multigene family. This protein has been found to form a linkage between desmin, which is a subunit of the IF network, and the extracellular matrix, and provides an important structural support in muscle. Two alternatively spliced variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

SYNM-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 15-99105901-A-AG is Benign according to our data. Variant chr15-99105901-A-AG is described in ClinVar as [Benign]. Clinvar id is 403504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNM	NM_145728.3	c.703dup	p.Glu235GlyfsTer40	frameshift_variant	1/4	ENST00000336292.11	NP_663780.2
SYNM-AS1	XR_001751810.2	n.84+1903_84+1904insC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNM	ENST00000336292.11	c.703dup	p.Glu235GlyfsTer40	frameshift_variant	1/4	1	NM_145728.3	ENSP00000336775	P3
SYNM	ENST00000328642.11	c.703dup	p.Glu235GlyfsTer40	frameshift_variant	1/4	1		ENSP00000330469	A2
SYNM	ENST00000594047.2	c.703dup	p.Glu235GlyfsTer40	frameshift_variant	1/5	1		ENSP00000472953	A2
SYNM	ENST00000560674.5	c.-49+7265dup		intron_variant		1		ENSP00000453040

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 1.00 AC: 131290 AN: 131292 Hom.: 65644 AF XY: 1.00 AC XY: 71716 AN XY: 71716

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 1.00 Hom.: 6701

Asia WGS AF: 0.999 AC: 3445 AN: 3450

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 10066/10118=99.4% -

SYNM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60530833; hg19: chr15-99646107;