dbSNP rs199660260: CD109:p.Thr251Lys (chr6-73759022-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_133493.5(CD109):c.752C>A(p.Thr251Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T251M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CD109
NM_133493.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.337

Publications

0 publications found

Variant links:

Genes affected

CD109 (HGNC:21685): (CD109 molecule) This gene encodes a glycosyl phosphatidylinositol (GPI)-linked glycoprotein that localizes to the surface of platelets, activated T-cells, and endothelial cells. The protein binds to and negatively regulates signalling by transforming growth factor beta (TGF-beta). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

CD109 links:

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ACMG classification

Classification was made for transcript

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=0.22395462).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133493.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD109	NM_133493.5	MANE Select	c.752C>A	p.Thr251Lys	missense	Exon 7 of 33	NP_598000.2	Q6YHK3-1
CD109	NM_001159587.3		c.752C>A	p.Thr251Lys	missense	Exon 7 of 33	NP_001153059.1	Q6YHK3-4
CD109	NM_001159588.3		c.521C>A	p.Thr174Lys	missense	Exon 6 of 32	NP_001153060.1	Q6YHK3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD109	ENST00000287097.6	TSL:1 MANE Select	c.752C>A	p.Thr251Lys	missense	Exon 7 of 33	ENSP00000287097.4	Q6YHK3-1
CD109	ENST00000437994.6	TSL:1	c.752C>A	p.Thr251Lys	missense	Exon 7 of 33	ENSP00000388062.2	Q6YHK3-4
CD109	ENST00000422508.6	TSL:1	c.521C>A	p.Thr174Lys	missense	Exon 6 of 32	ENSP00000404475.2	Q6YHK3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1433008

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

714798

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000304

AC:

AN:

32928

American (AMR)

AF:

0.00

AC:

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25876

East Asian (EAS)

AF:

0.00

AC:

AN:

39456

South Asian (SAS)

AF:

0.00

AC:

AN:

85078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086894

Other (OTH)

AF:

0.00

AC:

AN:

59474

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.7

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.0080

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.68

M_CAP

Benign

0.0069

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.34

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.31

Sift4G

Benign

0.38

Polyphen

0.75

Vest4

0.52

MutPred

0.62

Gain of ubiquitination at T251 (P = 0.0428)

MVP

0.092

MPC

0.035

ClinPred

0.16

GERP RS

-6.9

Varity_R

0.030

gMVP

0.45

Mutation Taster

=92/8

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over