Variant 15-51776937-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014548.4(TMOD2):c.412C>G(p.Leu138Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,324 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: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMOD2
NM_014548.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

Variant links:

Genes affected

TMOD2 (HGNC:11872): (tropomodulin 2) This gene encodes a neuronal-specific member of the tropomodulin family of actin-regulatory proteins. The encoded protein caps the pointed end of actin filaments preventing both elongation and depolymerization. The capping activity of this protein is dependent on its association with tropomyosin. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2008]

TMOD2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMOD2	NM_014548.4 linkuse as main transcript	c.412C>G	p.Leu138Val	missense_variant	5/10	ENST00000249700.9	NP_055363.1
TMOD2	NM_001142885.2 linkuse as main transcript	c.412C>G	p.Leu138Val	missense_variant	5/9		NP_001136357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMOD2	ENST00000249700.9 linkuse as main transcript	c.412C>G	p.Leu138Val	missense_variant	5/10	1	NM_014548.4	ENSP00000249700	P1	Q9NZR1-1
TMOD2	ENST00000435126.6 linkuse as main transcript	c.412C>G	p.Leu138Val	missense_variant	5/9	2		ENSP00000404590		Q9NZR1-2
TMOD2	ENST00000539962.6 linkuse as main transcript	c.280C>G	p.Leu94Val	missense_variant	6/11	2		ENSP00000437743
TMOD2	ENST00000560576.1 linkuse as main transcript	n.797-6492C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251364

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461324

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.412C>G (p.L138V) alteration is located in exon 5 (coding exon 4) of the TMOD2 gene. This alteration results from a C to G substitution at nucleotide position 412, causing the leucine (L) at amino acid position 138 to be replaced by a valine (V). 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

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.0

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

D;N;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.19

T;T;T

Polyphen

1.0

D;.;D

Vest4

0.68

MutPred

0.85

Gain of catalytic residue at L138 (P = 0.0095);.;Gain of catalytic residue at L138 (P = 0.0095);

MVP

0.62

MPC

0.25

ClinPred

0.86

GERP RS

5.6

Varity_R

0.69

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over