9-97568912-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003275.4(TMOD1):c.745A>G(p.Lys249Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 4.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23779386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMOD1	NM_003275.4	c.745A>G	p.Lys249Glu	missense_variant	8/10	ENST00000259365.9
TMOD1	NM_001166116.2	c.745A>G	p.Lys249Glu	missense_variant	8/10
TMOD1	XM_047423825.1	c.337A>G	p.Lys113Glu	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMOD1	ENST00000259365.9	c.745A>G	p.Lys249Glu	missense_variant	8/10	1	NM_003275.4	P1
TMOD1	ENST00000395211.6	c.745A>G	p.Lys249Glu	missense_variant	8/10	1		P1
TMOD1	ENST00000375175.1	c.364A>G	p.Lys122Glu	missense_variant	5/7	2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The c.745A>G (p.K249E) alteration is located in exon 8 (coding exon 7) of the TMOD1 gene. This alteration results from a A to G substitution at nucleotide position 745, causing the lysine (K) at amino acid position 249 to be replaced by a glutamic acid (E). 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	Benign	0.16
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.86	D;.;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;N;D
REVEL	Uncertain	0.48
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.37	B;B;.
Vest4		0.26
MutPred		0.57		Loss of ubiquitination at K249 (P = 0.0362);Loss of ubiquitination at K249 (P = 0.0362);.;
MVP		0.34
MPC		0.75
ClinPred		0.69	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.65

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: chr9-100331194;