15-51896471-C-A

Variant names:

• chr15-51896471-C-A
• rs200738333
• NM_014547.5:c.680C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014547.5(TMOD3):​c.680C>A​(p.Thr227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T227I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMOD3 NM_014547.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

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]

ENSG00000259201 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD3	NM_014547.5	c.680C>A	p.Thr227Lys	missense_variant	Exon 7 of 10	ENST00000308580.12	NP_055362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMOD3	ENST00000308580.12	c.680C>A	p.Thr227Lys	missense_variant	Exon 7 of 10	1	NM_014547.5	ENSP00000308753.7
TMOD3	ENST00000560549.5	n.263C>A		non_coding_transcript_exon_variant	Exon 5 of 12	1		ENSP00000454040.1
TMOD3	ENST00000561438.5	n.182C>A		non_coding_transcript_exon_variant	Exon 2 of 8	5		ENSP00000452939.1
ENSG00000259201	ENST00000558142.1	n.228+2541G>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461466 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727014

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111728

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.0038
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.085	T
Polyphen		0.0040	B
Vest4		0.84
MutPred		0.57		Loss of ubiquitination at K230 (P = 0.064);
MVP		0.14
MPC		0.081
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.68

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

Other links and lift over

dbSNP: rs200738333; hg19: chr15-52188668;