chrX-100594027-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_022144.3(TNMD):​c.313T>C​(p.Phe105Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,095,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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

11
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNMDNM_022144.3 linkc.313T>C p.Phe105Leu missense_variant Exon 3 of 7 ENST00000373031.5 NP_071427.2 Q9H2S6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNMDENST00000373031.5 linkc.313T>C p.Phe105Leu missense_variant Exon 3 of 7 1 NM_022144.3 ENSP00000362122.4 Q9H2S6-1
TNMDENST00000485971.1 linkn.404T>C non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
AF:
0.00000183
AC:
2
AN:
1095803
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
361255
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 02, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.313T>C (p.F105L) alteration is located in exon 3 (coding exon 3) of the TNMD gene. This alteration results from a T to C substitution at nucleotide position 313, causing the phenylalanine (F) at amino acid position 105 to be replaced by a leucine (L). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.80
MutPred
0.91
Loss of methylation at K106 (P = 0.0814);
MVP
0.92
MPC
1.1
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.94
gMVP
0.95

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: chrX-99849024; API