6-73696223-G-T

Variant names:

• chr6-73696223-G-T
• rs920184106
• NM_133493.5:c.8G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133493.5(CD109):​c.8G>T​(p.Gly3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000518 in 1,545,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: CD109 NM_133493.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

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-AS1 (HGNC:55765): (CD109 antisense RNA 1)

ACMG classification

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=0.08022174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD109	NM_133493.5	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 33	ENST00000287097.6	NP_598000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD109	ENST00000287097.6	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 33	1	NM_133493.5	ENSP00000287097.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000678 AC: 1 AN: 147520 AF XY: 0.0000125

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000502 AC: 7 AN: 1393280 Hom.: 0 Cov.: 31 AF XY: 0.00000581 AC XY: 4 AN XY: 688220

African (AFR) AF: 0.00 AC: 0 AN: 31348

American (AMR) AF: 0.00 AC: 0 AN: 36344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35866

South Asian (SAS) AF: 0.0000377 AC: 3 AN: 79474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1081740

Other (OTH) AF: 0.00 AC: 0 AN: 58056

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8G>T (p.G3V) alteration is located in exon 1 (coding exon 1) of the CD109 gene. This alteration results from a G to T substitution at nucleotide position 8, causing the glycine (G) at amino acid position 3 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	0.098
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0079	.;.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N
PhyloP100		1.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.075	T;D;D
Sift4G	Uncertain	0.058	T;D;D
Polyphen		0.69	P;P;P
Vest4		0.16
MutPred		0.28		Loss of glycosylation at P4 (P = 0.0518);Loss of glycosylation at P4 (P = 0.0518);Loss of glycosylation at P4 (P = 0.0518);
MVP		0.40
MPC		0.064
ClinPred		0.29	T
GERP RS		1.4
PromoterAI		-0.095	Neutral
Varity_R		0.059
gMVP		0.63
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs920184106; hg19: chr6-74405946;