rs754466306

Variant names:

• chr12-108591945-G-C
• rs754466306
• NM_181724.3:c.439C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-108591945-G-C
• chr12-108591945-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181724.3(TMEM119):​c.439C>G​(p.Pro147Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,822 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TMEM119 NM_181724.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.991
• Publications: 0 publications found

Genes affected

TMEM119 (HGNC:27884): (transmembrane protein 119) Involved in positive regulation of bone mineralization; positive regulation of osteoblast differentiation; and positive regulation of osteoblast proliferation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0778701).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181724.3. 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
	TMEM119	NM_181724.3	MANE Select	c.439C>G	p.Pro147Ala	missense	Exon 2 of 2	NP_859075.2	Q4V9L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM119	ENST00000392806.4	TSL:1 MANE Select	c.439C>G	p.Pro147Ala	missense	Exon 2 of 2	ENSP00000376553.3	Q4V9L6
	TMEM119	ENST00000861158.1		c.439C>G	p.Pro147Ala	missense	Exon 3 of 3	ENSP00000531217.1
	TMEM119	ENST00000861159.1		c.439C>G	p.Pro147Ala	missense	Exon 3 of 3	ENSP00000531218.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243578 AF XY: 0.00000752

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: 0.000169

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460704 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726638

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111526

Other (OTH) AF: 0.0000498 AC: 3 AN: 60292

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.99
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.067
Sift	Benign	0.40	T
Sift4G	Benign	0.87	T
Polyphen		0.24	B
Vest4		0.048
MutPred		0.21		Gain of catalytic residue at A144 (P = 0.0344)
MVP		0.061
MPC		0.15
ClinPred		0.090	T
GERP RS		2.6
Varity_R		0.057
gMVP		0.10
Mutation Taster		=86/14	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: rs754466306; hg19: chr12-108985721;