Genetic Variant TNMD:p.Ala238Ala (chrX-100599152-A-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_022144.3(TNMD):c.714A>C(p.Ala238Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,198,065 control chromosomes in the GnomAD database, including 6 homozygotes. There are 726 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 38 hem., cov: 23)

Exomes 𝑓: 0.0019 ( 6 hom. 688 hem. )

Consequence

TNMD
NM_022144.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.342

Publications

0 publications found

Variant links:

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]

TNMD links:

ENSG00000301679 (HGNC:):

ENSG00000301679 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-100599152-A-C is Benign according to our data. Variant chrX-100599152-A-C is described in ClinVar as [Benign]. Clinvar id is 729593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.342 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNMD	NM_022144.3 link	c.714A>C	p.Ala238Ala	synonymous_variant	Exon 6 of 7	ENST00000373031.5	NP_071427.2	Q9H2S6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNMD	ENST00000373031.5 link	c.714A>C	p.Ala238Ala	synonymous_variant	Exon 6 of 7	1	NM_022144.3	ENSP00000362122.4		Q9H2S6-1
ENSG00000301679	ENST00000780746.1 link	n.77+7042T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

130

AN:

111379

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000573

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000496

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00105

AC:

178

AN:

169039

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000238

Gnomad AMR exome

AF:

0.000480

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000639

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.000723

GnomAD4 exome

AF:

0.00189

AC:

2053

AN:

1086630

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

688

AN XY:

353180

show subpopulations

African (AFR)

AF:

0.000230

AC:

AN:

26062

American (AMR)

AF:

0.000413

AC:

AN:

33890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18989

East Asian (EAS)

AF:

0.00

AC:

AN:

29983

South Asian (SAS)

AF:

0.00372

AC:

190

AN:

51109

European-Finnish (FIN)

AF:

0.000347

AC:

AN:

40314

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4093

European-Non Finnish (NFE)

AF:

0.00211

AC:

1766

AN:

836593

Other (OTH)

AF:

0.00136

AC:

AN:

45597

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00117

AC:

130

AN:

111435

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

33617

show subpopulations

African (AFR)

AF:

0.000261

AC:

AN:

30610

American (AMR)

AF:

0.000572

AC:

AN:

10492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00270

AC:

AN:

2597

European-Finnish (FIN)

AF:

0.000496

AC:

AN:

6044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00200

AC:

106

AN:

53087

Other (OTH)

AF:

0.00

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.000990

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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chrX-100599152-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over