chrX-100599027-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022144.3(TNMD):​c.589C>G​(p.Gln197Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000335 in 1,193,384 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: TNMD NM_022144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11046687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNMD	NM_022144.3	c.589C>G	p.Gln197Glu	missense_variant	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>G	p.Gln197Glu	missense_variant	Exon 6 of 7	1	NM_022144.3	ENSP00000362122.4
ENSG00000301679	ENST00000780746.1	n.77+7167G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110957 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000601 AC: 1 AN: 166516 AF XY: 0.00

Gnomad AFR exome AF: 0.0000799

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082427 Hom.: 0 Cov.: 29 AF XY: 0.00000286 AC XY: 1 AN XY: 350019

African (AFR) AF: 0.0000773 AC: 2 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: 0.00 AC: 0 AN: 834429

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

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 110957 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33207

African (AFR) AF: 0.0000658 AC: 2 AN: 30390

American (AMR) AF: 0.00 AC: 0 AN: 10413

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2591

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5908

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53052

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.589C>G (p.Q197E) alteration is located in exon 6 (coding exon 6) of the TNMD gene. This alteration results from a C to G substitution at nucleotide position 589, causing the glutamine (Q) at amino acid position 197 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	0.065
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.035
Sift	Benign	0.079	T
Sift4G	Benign	0.75	T
Polyphen		0.010	B
Vest4		0.18
MutPred		0.21		Gain of disorder (P = 0.0606);
MVP		0.19
MPC		0.34
ClinPred		0.092	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.45
Mutation Taster		=83/17	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: rs1353786968; hg19: chrX-99854024;