Genetic Variant SYNM:p.Thr644Ser (chr15-99130291-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_145728.3(SYNM):c.1931C>G(p.Thr644Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T644I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SYNM
NM_145728.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.11

Publications

0 publications found

Variant links:

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 links:

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

SYNM-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11018941).

BP6

Variant 15-99130291-C-G is Benign according to our data. Variant chr15-99130291-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2224283.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1931C>G	p.Thr644Ser	missense	Exon 4 of 4	NP_663780.2	O15061-1
	SYNM	NM_015286.6		c.1931C>G	p.Thr644Ser	missense	Exon 4 of 5	NP_056101.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNM	ENST00000336292.11	TSL:1 MANE Select	c.1931C>G	p.Thr644Ser	missense	Exon 4 of 4	ENSP00000336775.7	O15061-1
SYNM	ENST00000594047.2	TSL:1	c.1931C>G	p.Thr644Ser	missense	Exon 4 of 5	ENSP00000472953.1	O15061-2
SYNM	ENST00000560674.5	TSL:1	c.1073C>G	p.Thr358Ser	missense	Exon 4 of 5	ENSP00000453040.1	H0YL34

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111856

Other (OTH)

AF:

0.0000166

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0055

Eigen

Benign

-0.11

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.56

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

PhyloP100

4.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.24

REVEL

Benign

0.12

Sift

Benign

0.61

Sift4G

Benign

1.0

Vest4

0.034

MutPred

0.30

Loss of helix (P = 0.0068)

MVP

0.21

MPC

0.14

ClinPred

0.36

GERP RS

5.9

gMVP

0.14

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over