X-100585333-A-G

Variant names:

• chrX-100585333-A-G
• NM_022144.3:c.151A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022144.3(TNMD):​c.151A>G​(p.Lys51Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TNMD NM_022144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36
• Publications: 0 publications found

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]

ENSG00000301679 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNMD	NM_022144.3	c.151A>G	p.Lys51Glu	missense_variant	Exon 2 of 7	ENST00000373031.5	NP_071427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNMD	ENST00000373031.5	c.151A>G	p.Lys51Glu	missense_variant	Exon 2 of 7	1	NM_022144.3	ENSP00000362122.4
ENSG00000301679	ENST00000780746.1	n.77+20861T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.151A>G (p.K51E) alteration is located in exon 2 (coding exon 2) of the TNMD gene. This alteration results from a A to G substitution at nucleotide position 151, causing the lysine (K) at amino acid position 51 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	0.20
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.98	D
Vest4		0.54
MutPred		0.44		Loss of methylation at K51 (P = 0.0028);
MVP		0.56
MPC		1.1
ClinPred		0.82	D
GERP RS		5.3
PromoterAI		-0.0086	Neutral
Varity_R		0.40
gMVP		0.85
Mutation Taster		=86/14	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

hg19: chrX-99840330;