X-100594317-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022144.3(TNMD):c.378T>G(p.Ile126Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,086,968 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

TNMD
NM_022144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0330

Publications

0 publications found

Variant links:

Genes affected

TNMD (HGNC:17757): (tenomodulin) This gene encodes a protein that is related to chondromodulin-I, which is a cartilage-specific glycoprotein that functions to stimulate chondrocyte growth and to inhibit tube formation of endothelial cells. This protein is also an angiogenesis inhibitor. Genetic variation in this gene is associated with a risk for type 2 diabetes, central obesity and serum levels of systemic immune mediators in a body size-dependent manner. This gene is also a candidate gene for age-related macular degeneration, though a direct link has yet to be demonstrated. [provided by RefSeq, Sep 2009]

TNMD links:

ENSG00000301679 (HGNC:):

ENSG00000301679 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29740933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNMD	NM_022144.3 link	c.378T>G	p.Ile126Met	missense_variant	Exon 4 of 7	ENST00000373031.5	NP_071427.2	Q9H2S6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNMD	ENST00000373031.5 link	c.378T>G	p.Ile126Met	missense_variant	Exon 4 of 7	1	NM_022144.3	ENSP00000362122.4	Q9H2S6-1
TNMD	ENST00000485971.1 link	n.469T>G		non_coding_transcript_exon_variant	Exon 2 of 3	3
ENSG00000301679	ENST00000780746.1 link	n.77+11877A>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000560

AC:

AN:

178679

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000739

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1086968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353256

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26241

American (AMR)

AF:

0.00

AC:

AN:

34794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19194

East Asian (EAS)

AF:

0.0000666

AC:

AN:

30008

South Asian (SAS)

AF:

0.00

AC:

AN:

52217

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4096

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834478

Other (OTH)

AF:

0.00

AC:

AN:

45666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.378T>G (p.I126M) alteration is located in exon 4 (coding exon 4) of the TNMD gene. This alteration results from a T to G substitution at nucleotide position 378, causing the isoleucine (I) at amino acid position 126 to be replaced by a methionine (M). 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

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.75

M_CAP

Benign

0.036

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.2

PhyloP100

-0.033

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.87

REVEL

Uncertain

0.38

Sift

Uncertain

0.028

Sift4G

Benign

0.062

Polyphen

0.83

Vest4

0.30

MutPred

0.33

Loss of methylation at K127 (P = 0.0626);

MVP

0.36

MPC

0.80

ClinPred

0.29

GERP RS

-1.1

Varity_R

0.23

gMVP

0.61

Mutation Taster

=91/9

polymorphism

(source)

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

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X-100594317-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over