15-99130022-C-G

Variant names:

• chr15-99130022-C-G
• NM_145728.3:c.1662C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145728.3(SYNM):​c.1662C>G​(p.Ser554Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNM NM_145728.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.312
• Publications: 0 publications found

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-AS2 (HGNC:56228): (SYNM antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09925398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145728.3. 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
	SYNM	NM_145728.3	MANE Select	c.1662C>G	p.Ser554Arg	missense	Exon 4 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.1662C>G	p.Ser554Arg	missense	Exon 4 of 5	NP_056101.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNM	ENST00000336292.11	TSL:1 MANE Select	c.1662C>G	p.Ser554Arg	missense	Exon 4 of 4	ENSP00000336775.7	O15061-1
	SYNM	ENST00000594047.2	TSL:1	c.1662C>G	p.Ser554Arg	missense	Exon 4 of 5	ENSP00000472953.1	O15061-2
	SYNM	ENST00000560674.5	TSL:1	c.804C>G	p.Ser268Arg	missense	Exon 4 of 5	ENSP00000453040.1	H0YL34

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.31
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.091
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Vest4		0.19
MutPred		0.22		Loss of phosphorylation at S554 (P = 0.0017)
MVP		0.49
MPC		0.41
ClinPred		0.54	D
GERP RS		3.7
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr15-99670227;