X-100599027-C-T

Variant names:

• chrX-100599027-C-T
• rs1353786968
• NM_022144.3:c.589C>T

Variant summary

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

The NM_022144.3(TNMD):​c.589C>T​(p.Gln197*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,427 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: TNMD NM_022144.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• 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.589C>T	p.Gln197*	stop_gained	Exon 6 of 7	ENST00000373031.5	NP_071427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNMD	ENST00000373031.5	c.589C>T	p.Gln197*	stop_gained	Exon 6 of 7	1	NM_022144.3	ENSP00000362122.4
ENSG00000301679	ENST00000780746.1	n.77+7167G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082427 Hom.: 0 Cov.: 29 AF XY: 0.00000286 AC XY: 1 AN XY: 350019

African (AFR) AF: 0.00 AC: 0 AN: 25868

American (AMR) AF: 0.00 AC: 0 AN: 33499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18789

East Asian (EAS) AF: 0.00 AC: 0 AN: 29869

South Asian (SAS) AF: 0.00 AC: 0 AN: 50303

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4059

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834429

Other (OTH) AF: 0.00 AC: 0 AN: 45383

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.70	D
PhyloP100		2.3
Vest4		0.82
GERP RS		5.8
Mutation Taster		=8/192	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1353786968; hg19: chrX-99854024;