NM_003275.4:c.140G>C

Variant names:

• chr9-97546204-G-C
• rs767864969
• NM_003275.4:c.140G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_003275.4(TMOD1):​c.140G>C​(p.Gly47Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,208 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: 0.0000096 (0 hom.)
• Consequence: TMOD1 NM_003275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

TMOD1 (HGNC:11871): (tropomodulin 1) This gene encodes a member of the tropomodulin family. The encoded protein is an actin-capping protein that regulates tropomyosin by binding to its N-terminus, inhibiting depolymerization and elongation of the pointed end of actin filaments and thereby influencing the structure of the erythrocyte membrane skeleton. Multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

TMOD1 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003275.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMOD1	NM_003275.4	MANE Select	c.140G>C	p.Gly47Ala	missense	Exon 3 of 10	NP_003266.1	P28289-1
	TMOD1	NM_001166116.2		c.140G>C	p.Gly47Ala	missense	Exon 3 of 10	NP_001159588.1	P28289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMOD1	ENST00000259365.9	TSL:1 MANE Select	c.140G>C	p.Gly47Ala	missense	Exon 3 of 10	ENSP00000259365.3	P28289-1
	TMOD1	ENST00000395211.6	TSL:1	c.140G>C	p.Gly47Ala	missense	Exon 3 of 10	ENSP00000378637.2	P28289-1
	TMOD1	ENST00000950655.1		c.140G>C	p.Gly47Ala	missense	Exon 3 of 12	ENSP00000620714.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000562 AC: 14 AN: 248896 AF XY: 0.0000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000958 AC: 14 AN: 1461208 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726912

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.000291 AC: 13 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.75		Gain of loop (P = 0.0851)
MVP		0.23
MPC		1.1
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.41
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs767864969; hg19: chr9-100308486;