6-73765967-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_133493.5(CD109):c.1145T>C(p.Leu382Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,048 control chromosomes in the GnomAD database, including 1 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: CD109 NM_133493.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005872011).
• BP6: Variant 6-73765967-T-C is Benign according to our data. Variant chr6-73765967-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2385237.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD109	NM_133493.5	c.1145T>C	p.Leu382Pro	missense_variant	11/33	ENST00000287097.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD109	ENST00000287097.6	c.1145T>C	p.Leu382Pro	missense_variant	11/33	1	NM_133493.5	P1
CD109	ENST00000437994.6	c.1145T>C	p.Leu382Pro	missense_variant	11/33	1
CD109	ENST00000422508.6	c.914T>C	p.Leu305Pro	missense_variant	10/32	1
CD109	ENST00000649530.1	n.1117T>C		non_coding_transcript_exon_variant	10/26

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 251036 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135660

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727180

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152280 Hom.: 1 Cov.: 31 AF XY: 0.000591 AC XY: 44 AN XY: 74456

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000794 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.20
Dann	Benign	0.54
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.75	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.78	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.12
MVP		0.17
MPC		0.041
ClinPred		0.0048	T
GERP RS		-9.4
Varity_R		0.033
gMVP		0.54

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: rs146419763; hg19: chr6-74475690; COSMIC: COSV54659542;