9-97564106-A-G

Variant names:

• chr9-97564106-A-G
• NM_003275.4:c.556A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003275.4(TMOD1):​c.556A>G​(p.Thr186Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMOD1 NM_003275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD1	NM_003275.4	c.556A>G	p.Thr186Ala	missense_variant	Exon 6 of 10	ENST00000259365.9	NP_003266.1
TMOD1	NM_001166116.2	c.556A>G	p.Thr186Ala	missense_variant	Exon 6 of 10		NP_001159588.1
TMOD1	XM_047423825.1	c.148A>G	p.Thr50Ala	missense_variant	Exon 4 of 8		XP_047279781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMOD1	ENST00000259365.9	c.556A>G	p.Thr186Ala	missense_variant	Exon 6 of 10	1	NM_003275.4	ENSP00000259365.3
TMOD1	ENST00000395211.6	c.556A>G	p.Thr186Ala	missense_variant	Exon 6 of 10	1		ENSP00000378637.2
TMOD1	ENST00000375175.1	c.175A>G	p.Thr59Ala	missense_variant	Exon 3 of 7	2		ENSP00000364318.1

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

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556A>G (p.T186A) alteration is located in exon 6 (coding exon 5) of the TMOD1 gene. This alteration results from a A to G substitution at nucleotide position 556, causing the threonine (T) at amino acid position 186 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.56	P;P;.
Vest4		0.89
MutPred		0.41		Loss of phosphorylation at T186 (P = 0.0382);Loss of phosphorylation at T186 (P = 0.0382);.;
MVP		0.83
MPC		0.46
ClinPred		0.82	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.61

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: chr9-100326388;