rs749960538

Variant names:

• chr6-73696252-C-A
• rs749960538
• NM_133493.5:c.37C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-73696252-C-A
• chr6-73696252-C-G
• chr6-73696252-C-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.37C>A​(p.Leu13Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CD109 NM_133493.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• 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=0.07692179).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133493.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD109	NM_133493.5	MANE Select	c.37C>A	p.Leu13Ile	missense	Exon 1 of 33	NP_598000.2	Q6YHK3-1
	CD109	NM_001159587.3		c.37C>A	p.Leu13Ile	missense	Exon 1 of 33	NP_001153059.1	Q6YHK3-4
	CD109	NM_001159588.3		c.37C>A	p.Leu13Ile	missense	Exon 1 of 32	NP_001153060.1	Q6YHK3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD109	ENST00000287097.6	TSL:1 MANE Select	c.37C>A	p.Leu13Ile	missense	Exon 1 of 33	ENSP00000287097.4	Q6YHK3-1
	CD109	ENST00000437994.6	TSL:1	c.37C>A	p.Leu13Ile	missense	Exon 1 of 33	ENSP00000388062.2	Q6YHK3-4
	CD109	ENST00000422508.6	TSL:1	c.37C>A	p.Leu13Ile	missense	Exon 1 of 32	ENSP00000404475.2	Q6YHK3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388832 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30924

American (AMR) AF: 0.00 AC: 0 AN: 36112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25030

East Asian (EAS) AF: 0.00 AC: 0 AN: 35506

South Asian (SAS) AF: 0.00 AC: 0 AN: 79326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080454

Other (OTH) AF: 0.00 AC: 0 AN: 57880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.38
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.024
Sift	Benign	0.065	T
Sift4G	Benign	0.15	T
Polyphen		0.054	B
Vest4		0.070
MutPred		0.55		Gain of helix (P = 0.0164)
MVP		0.099
MPC		0.035
ClinPred		0.19	T
GERP RS		1.6
PromoterAI		0.013	Neutral
Varity_R		0.080
gMVP		0.33
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs749960538; hg19: chr6-74405975;