dbSNP rs746856695: TMOD3:p.Ala278Gly (chr15-51900252-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014547.5(TMOD3):c.833C>G(p.Ala278Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A278V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMOD3
NM_014547.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

Publications

0 publications found

Variant links:

Genes affected

TMOD3 (HGNC:11873): (tropomodulin 3) Enables cadherin binding activity involved in cell-cell adhesion. Predicted to be involved in actin filament organization; muscle contraction; and myofibril assembly. Predicted to act upstream of or within actin cytoskeleton organization; erythrocyte development; and positive regulation of mitotic cell cycle phase transition. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

TMOD3 links:

ENSG00000259201 (HGNC:):

ENSG00000259201 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD3	NM_014547.5 link	c.833C>G	p.Ala278Gly	missense_variant	Exon 8 of 10	ENST00000308580.12	NP_055362.1	Q9NYL9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMOD3	ENST00000308580.12 link	c.833C>G	p.Ala278Gly	missense_variant	Exon 8 of 10	1	NM_014547.5	ENSP00000308753.7	Q9NYL9
TMOD3	ENST00000560549.5 link	n.416C>G		non_coding_transcript_exon_variant	Exon 6 of 12	1		ENSP00000454040.1	H0YNJ8
TMOD3	ENST00000561438.5 link	n.335C>G		non_coding_transcript_exon_variant	Exon 3 of 8	5		ENSP00000452939.1	H0YKU1
ENSG00000259201	ENST00000558142.1 link	n.105+767G>C		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.5

PhyloP100

6.2

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.51

MutPred

0.82

Loss of stability (P = 0.0164);

MVP

0.26

MPC

0.054

ClinPred

0.97

GERP RS

5.6

Varity_R

0.59

gMVP

0.55

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs746856695

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over