Genetic Variant NM_024893.3:c.136C>A (chr20-24543233-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024893.3(SYNDIG1):c.136C>A(p.Pro46Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SYNDIG1
NM_024893.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.63

Publications

0 publications found

Variant links:

Genes affected

SYNDIG1 (HGNC:15885): (synapse differentiation inducing 1) This gene encodes a protein that belongs to the interferon-induced transmembrane family of proteins. A similar protein in rat is thought to regulate the development of excitatory synapses. [provided by RefSeq, Jul 2013]

SYNDIG1 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SYNDIG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024893.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNDIG1	NM_024893.3	MANE Select	c.136C>A	p.Pro46Thr	missense	Exon 2 of 4	NP_079169.1	Q9H7V2
SYNDIG1	NM_001323606.2		c.136C>A	p.Pro46Thr	missense	Exon 3 of 5	NP_001310535.1	Q9H7V2
SYNDIG1	NM_001323607.2		c.136C>A	p.Pro46Thr	missense	Exon 2 of 4	NP_001310536.1	Q9H7V2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNDIG1	ENST00000376862.4	TSL:1 MANE Select	c.136C>A	p.Pro46Thr	missense	Exon 2 of 4	ENSP00000366058.3	Q9H7V2
SYNDIG1	ENST00000892834.1		c.136C>A	p.Pro46Thr	missense	Exon 3 of 5	ENSP00000562893.1
SYNDIG1	ENST00000892835.1		c.136C>A	p.Pro46Thr	missense	Exon 3 of 5	ENSP00000562894.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.13

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.7

PhyloP100

6.6

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.56

Sift

Uncertain

0.012

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.67

MutPred

0.33

Gain of glycosylation at P46 (P = 0.0871)

MVP

0.85

MPC

0.99

ClinPred

0.96

GERP RS

6.0

Varity_R

0.24

gMVP

0.35

Mutation Taster

=47/53

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over