6-73766068-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_133493.5(CD109):c.1246C>G(p.Gln416Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,613,958 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q416H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: CD109 NM_133493.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.47

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073144436).
• BP6: Variant 6-73766068-C-G is Benign according to our data. Variant chr6-73766068-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 773471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD109	NM_133493.5	c.1246C>G	p.Gln416Glu	missense_variant	11/33	ENST00000287097.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD109	ENST00000287097.6	c.1246C>G	p.Gln416Glu	missense_variant	11/33	1	NM_133493.5	P1
CD109	ENST00000437994.6	c.1246C>G	p.Gln416Glu	missense_variant	11/33	1
CD109	ENST00000422508.6	c.1015C>G	p.Gln339Glu	missense_variant	10/32	1
CD109	ENST00000649530.1	n.1218C>G		non_coding_transcript_exon_variant	10/26

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152096 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00220 AC: 552 AN: 251426 Hom.: 1 AF XY: 0.00216 AC XY: 293 AN XY: 135894

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00370 AC: 5415 AN: 1461744 Hom.: 16 Cov.: 31 AF XY: 0.00354 AC XY: 2576 AN XY: 727182

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00471

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152214 Hom.: 1 Cov.: 31 AF XY: 0.00189 AC XY: 141 AN XY: 74424

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00342 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00373

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CD109: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jun 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.4
Dann	Benign	0.94
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.71	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.061	B;B;B
Vest4		0.13
MVP		0.25
MPC		0.032
ClinPred		0.021	T
GERP RS		3.6
Varity_R		0.090
gMVP		0.36

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: rs113690012; hg19: chr6-74475791; COSMIC: COSV54658523;