6-73763626-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133493.5(CD109):c.1048A>G(p.Ile350Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,444,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CD109 NM_133493.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.715

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07172835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD109	NM_133493.5	c.1048A>G	p.Ile350Val	missense_variant	10/33	ENST00000287097.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD109	ENST00000287097.6	c.1048A>G	p.Ile350Val	missense_variant	10/33	1	NM_133493.5	P1
CD109	ENST00000437994.6	c.1048A>G	p.Ile350Val	missense_variant	10/33	1
CD109	ENST00000422508.6	c.817A>G	p.Ile273Val	missense_variant	9/32	1
CD109	ENST00000649530.1	n.1020A>G		non_coding_transcript_exon_variant	9/26

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000817 AC: 2 AN: 244908 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1444886 Hom.: 0 Cov.: 27 AF XY: 0.00000697 AC XY: 5 AN XY: 717832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000816

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1048A>G (p.I350V) alteration is located in exon 10 (coding exon 10) of the CD109 gene. This alteration results from a A to G substitution at nucleotide position 1048, causing the isoleucine (I) at amino acid position 350 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	0.083
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	10
Dann	Benign	0.50
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.17	B;B;B
Vest4		0.26
MutPred		0.39		.;Gain of catalytic residue at I350 (P = 0.08);Gain of catalytic residue at I350 (P = 0.08);
MVP		0.067
MPC		0.028
ClinPred		0.050	T
GERP RS		0.17
Varity_R		0.017
gMVP		0.24

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: rs912040605; hg19: chr6-74473349; COSMIC: COSV54649860;