chr9-97568978-C-T

Variant names:

• chr9-97568978-C-T
• rs375913710
• NM_003275.4:c.811C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003275.4(TMOD1):​c.811C>T​(p.Arg271Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TMOD1 NM_003275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24478269).

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.811C>T	p.Arg271Cys	missense	Exon 8 of 10	NP_003266.1	P28289-1
	TMOD1	NM_001166116.2		c.811C>T	p.Arg271Cys	missense	Exon 8 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.811C>T	p.Arg271Cys	missense	Exon 8 of 10	ENSP00000259365.3	P28289-1
	TMOD1	ENST00000395211.6	TSL:1	c.811C>T	p.Arg271Cys	missense	Exon 8 of 10	ENSP00000378637.2	P28289-1
	TMOD1	ENST00000950655.1		c.934C>T	p.Arg312Cys	missense	Exon 9 of 12	ENSP00000620714.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251484 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727230

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	Benign	0.081
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.19	B
Vest4		0.25
MVP		0.18
MPC		0.54
ClinPred		0.12	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.52
Mutation Taster		=64/36	polymorphism

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: rs375913710; hg19: chr9-100331260; COSMIC: COSV99404295;