Genetic Variant TMOD3:p.Ala136Gly (chr15-51889056-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.407C>G(p.Ala136Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000283 in 1,412,310 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar 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: 0.9828

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD3	NM_014547.5 link	c.407C>G	p.Ala136Gly	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>G	p.Ala136Gly	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_014547.5	ENSP00000308753.7	Q9NYL9
TMOD3	ENST00000560549.5 link	n.-11C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 12	1		ENSP00000454040.1	H0YNJ8
TMOD3	ENST00000560549.5 link	n.-11C>G		5_prime_UTR_variant	Exon 3 of 12	1		ENSP00000454040.1	H0YNJ8
ENSG00000259201	ENST00000558142.1 link	n.352-1338G>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1412310

Hom.:

Cov.:

AF XY:

0.00

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:

0.00

AC:

AN:

79122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1089370

Other (OTH)

AF:

0.00

AC:

AN:

58472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.407C>G (p.A136G) alteration is located in exon 5 (coding exon 4) of the TMOD3 gene. This alteration results from a C to G substitution at nucleotide position 407, causing the alanine (A) at amino acid position 136 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

6.3

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.21

Sift

Benign

0.044

Sift4G

Benign

0.16

Polyphen

0.25

Vest4

0.66

MutPred

0.93

Loss of stability (P = 0.0536);

MVP

0.14

MPC

0.16

ClinPred

0.94

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.50

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.63

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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15-51889056-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over