Genetic Variant NM_133493.5:c.1130G>A (chr6-73765952-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_133493.5(CD109):c.1130G>A(p.Gly377Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00764 in 1,613,654 control chromosomes in the GnomAD database, including 62 homozygotes. 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 Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 56 hom. )

Consequence

CD109
NM_133493.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.78

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003906667).

BP6

Variant 6-73765952-G-A is Benign according to our data. Variant chr6-73765952-G-A is described in ClinVar as [Benign]. Clinvar id is 1879664.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD109	NM_133493.5 link	c.1130G>A	p.Gly377Asp	missense_variant	Exon 11 of 33	ENST00000287097.6	NP_598000.2	Q6YHK3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CD109	ENST00000287097.6 link	c.1130G>A	p.Gly377Asp	missense_variant	Exon 11 of 33	1	NM_133493.5	ENSP00000287097.4	Q6YHK3-1
CD109	ENST00000437994.6 link	c.1130G>A	p.Gly377Asp	missense_variant	Exon 11 of 33	1		ENSP00000388062.2	Q6YHK3-4
CD109	ENST00000422508.6 link	c.899G>A	p.Gly300Asp	missense_variant	Exon 10 of 32	1		ENSP00000404475.2	Q6YHK3-2
CD109	ENST00000649530.1 link	n.1102G>A		non_coding_transcript_exon_variant	Exon 10 of 26

Frequencies

GnomAD3 genomes

AF:

0.00688

AC:

1046

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00826

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00857

AC:

2147

AN:

250640

Hom.:

AF XY:

0.00920

AC XY:

1246

AN XY:

135442

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.00858

Gnomad OTH exome

AF:

0.00802

GnomAD4 exome

AF:

0.00772

AC:

11285

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

5804

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00591

Gnomad4 ASJ exome

AF:

0.00318

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0130

Gnomad4 FIN exome

AF:

0.0196

Gnomad4 NFE exome

AF:

0.00734

Gnomad4 OTH exome

AF:

0.00800

GnomAD4 genome

AF:

0.00687

AC:

1046

AN:

152232

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

552

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0131

Gnomad4 FIN

AF:

0.0169

Gnomad4 NFE

AF:

0.00828

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00694

Hom.:

Bravo

AF:

0.00561

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00890

AC:

1081

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00824

EpiControl

AF:

0.00942

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CD109: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.077

.;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.85

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;M;M

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Benign

0.076

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.99

D;B;P

Vest4

0.33

MVP

0.49

MPC

0.043

ClinPred

0.026

GERP RS

2.9

Varity_R

0.091

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over