X-100585294-A-G

Position:

• chrX-100585294-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022144.3(TNMD):​c.112A>G​(p.Ile38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,209,005 control chromosomes in the GnomAD database, including 3 homozygotes. There are 626 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 48 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (3 hom. 578 hem.)
• Consequence: TNMD NM_022144.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.665

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008528352).
• BP6: Variant X-100585294-A-G is Benign according to our data. Variant chrX-100585294-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 773792.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 48 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNMD	NM_022144.3	c.112A>G	p.Ile38Val	missense_variant	2/7	ENST00000373031.5	NP_071427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNMD	ENST00000373031.5	c.112A>G	p.Ile38Val	missense_variant	2/7	1	NM_022144.3	ENSP00000362122.4

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 146 AN: 111840 Hom.: 0 Cov.: 23 AF XY: 0.00141 AC XY: 48 AN XY: 34020

Gnomad AFR AF: 0.000292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00119 AC: 218 AN: 182768 Hom.: 0 AF XY: 0.00131 AC XY: 88 AN XY: 67404

Gnomad AFR exome AF: 0.000609

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000211

Gnomad FIN exome AF: 0.00275

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00165 AC: 1812 AN: 1097112 Hom.: 3 Cov.: 29 AF XY: 0.00159 AC XY: 578 AN XY: 362636

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.00252

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00130 AC: 146 AN: 111893 Hom.: 0 Cov.: 23 AF XY: 0.00141 AC XY: 48 AN XY: 34083

Gnomad4 AFR AF: 0.000292

Gnomad4 AMR AF: 0.000380

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00215

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00169 Hom.: 75

Bravo AF: 0.00108

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00193 AC: 13

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2021

The c.112A>G (p.I38V) 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 112, causing the isoleucine (I) at amino acid position 38 to be replaced by a valine (V). 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	0.064
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.7
DANN	Benign	0.53
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.087
Sift	Benign	0.99	T
Sift4G	Benign	0.90	T
Polyphen		0.0080	B
Vest4		0.034
MVP		0.12
MPC		0.24
ClinPred		0.0099	T
GERP RS		5.2
Varity_R		0.047
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs141371868; hg19: chrX-99840291; COSMIC: COSV65977237;