chr9-97565932-C-G

Variant names:

• chr9-97565932-C-G
• rs144800521
• NM_003275.4:c.703C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003275.4(TMOD1):​c.703C>G​(p.Arg235Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R235Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMOD1 NM_003275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.979
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

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.703C>G	p.Arg235Gly	missense	Exon 7 of 10	NP_003266.1	P28289-1
	TMOD1	NM_001166116.2		c.703C>G	p.Arg235Gly	missense	Exon 7 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.703C>G	p.Arg235Gly	missense	Exon 7 of 10	ENSP00000259365.3	P28289-1
	TMOD1	ENST00000395211.6	TSL:1	c.703C>G	p.Arg235Gly	missense	Exon 7 of 10	ENSP00000378637.2	P28289-1
	TMOD1	ENST00000950655.1		c.826C>G	p.Arg276Gly	missense	Exon 8 of 12	ENSP00000620714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.98
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.66
Sift	Benign	0.35	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.84
MutPred		0.57		Loss of MoRF binding (P = 0.0345)
MVP		0.71
MPC		0.70
ClinPred		0.96	D
GERP RS		0.66
Varity_R		0.61
gMVP		0.71
Mutation Taster		=52/48	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: rs144800521; hg19: chr9-100328214;