chr15-51901907-A-G

Position:

• chr15-51901907-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014547.5(TMOD3):​c.895A>G​(p.Thr299Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMOD3 NM_014547.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3785785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMOD3	NM_014547.5	c.895A>G	p.Thr299Ala	missense_variant	9/10	ENST00000308580.12	NP_055362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMOD3	ENST00000308580.12	c.895A>G	p.Thr299Ala	missense_variant	9/10	1	NM_014547.5	ENSP00000308753	P1
TMOD3	ENST00000560549.5	c.478A>G	p.Thr160Ala	missense_variant, NMD_transcript_variant	7/12	1		ENSP00000454040
TMOD3	ENST00000560725.1	n.243A>G		non_coding_transcript_exon_variant	2/4	4
TMOD3	ENST00000561438.5	c.400A>G	p.Thr134Ala	missense_variant, NMD_transcript_variant	4/8	5		ENSP00000452939

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.895A>G (p.T299A) alteration is located in exon 9 (coding exon 8) of the TMOD3 gene. This alteration results from a A to G substitution at nucleotide position 895, causing the threonine (T) at amino acid position 299 to be replaced by an alanine (A). 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	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.36		Loss of phosphorylation at T299 (P = 0.0607);
MVP		0.10
MPC		0.055
ClinPred		0.79	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-52194104;