X-100594282-G-A

Variant names:

• chrX-100594282-G-A
• rs1248597873
• NM_022144.3:c.343G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_022144.3(TNMD):​c.343G>A​(p.Val115Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,195,426 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V115V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: TNMD NM_022144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNMD	NM_022144.3	c.343G>A	p.Val115Met	missense_variant	Exon 4 of 7	ENST00000373031.5	NP_071427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNMD	ENST00000373031.5	c.343G>A	p.Val115Met	missense_variant	Exon 4 of 7	1	NM_022144.3	ENSP00000362122.4
TNMD	ENST00000485971.1	n.434G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3
ENSG00000301679	ENST00000780746.1	n.77+11912C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00000910 AC: 1 AN: 109851 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000170 AC: 3 AN: 176321 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 13 AN: 1085575 Hom.: 0 Cov.: 27 AF XY: 0.00000852 AC XY: 3 AN XY: 352171

African (AFR) AF: 0.00 AC: 0 AN: 26185

American (AMR) AF: 0.0000289 AC: 1 AN: 34629

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19103

East Asian (EAS) AF: 0.00 AC: 0 AN: 30005

South Asian (SAS) AF: 0.0000387 AC: 2 AN: 51657

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.0000108 AC: 9 AN: 833996

Other (OTH) AF: 0.00 AC: 0 AN: 45647

GnomAD4 genome AF: 0.00000910 AC: 1 AN: 109851 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32095

African (AFR) AF: 0.00 AC: 0 AN: 30169

American (AMR) AF: 0.00 AC: 0 AN: 10244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2501

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52719

Other (OTH) AF: 0.00 AC: 0 AN: 1467

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343G>A (p.V115M) alteration is located in exon 4 (coding exon 4) of the TNMD gene. This alteration results from a G to A substitution at nucleotide position 343, causing the valine (V) at amino acid position 115 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	0.26
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.52		Loss of catalytic residue at V115 (P = 0.022);
MVP		0.69
MPC		0.47
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.29
gMVP		0.82
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs1248597873; hg19: chrX-99849279;