Genetic Variant TMOD3:p.Ala136Glu (chr15-51889056-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_014547.5(TMOD3):c.407C>A(p.Ala136Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000283 in 1,412,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A136G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TMOD3
NM_014547.5 missense, splice_region

Scores

Splicing: ADA: 0.9680

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.29

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD3	NM_014547.5 link	c.407C>A	p.Ala136Glu	missense_variant, splice_region_variant	Exon 5 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.407C>A	p.Ala136Glu	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_014547.5	ENSP00000308753.7	Q9NYL9
TMOD3	ENST00000560549.5 link	n.-11C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 12	1		ENSP00000454040.1	H0YNJ8
TMOD3	ENST00000560549.5 link	n.-11C>A		5_prime_UTR_variant	Exon 3 of 12	1		ENSP00000454040.1	H0YNJ8
ENSG00000259201	ENST00000558142.1 link	n.352-1338G>T		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1412306

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

703626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30194

American (AMR)

AF:

0.00

AC:

AN:

33408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24874

East Asian (EAS)

AF:

0.00

AC:

AN:

38096

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53128

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089368

Other (OTH)

AF:

0.00

AC:

AN:

58472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.7

PhyloP100

6.3

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

0.99

Vest4

0.78

MutPred

0.91

Gain of relative solvent accessibility (P = 0.09);

MVP

0.35

MPC

0.37

ClinPred

0.99

GERP RS

5.8

Varity_R

0.89

gMVP

0.82

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.80

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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chr15-51889056-C-A

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