chr12-108591702-T-A

Variant names:

• chr12-108591702-T-A
• NM_181724.3:c.682A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181724.3(TMEM119):​c.682A>T​(p.Thr228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM119 NM_181724.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.250
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030951053).

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.682A>T	p.Thr228Ser	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.682A>T	p.Thr228Ser	missense	Exon 2 of 2	ENSP00000376553.3	Q4V9L6
	TMEM119	ENST00000861158.1		c.682A>T	p.Thr228Ser	missense	Exon 3 of 3	ENSP00000531217.1
	TMEM119	ENST00000861159.1		c.682A>T	p.Thr228Ser	missense	Exon 3 of 3	ENSP00000531218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.091
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.95
DANN	Benign	0.23
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.25
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.052
Sift	Benign	0.11	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.020
MutPred		0.11		Gain of catalytic residue at V224 (P = 0.0143)
MVP		0.030
MPC		0.12
ClinPred		0.030	T
GERP RS		3.4
Varity_R		0.041
gMVP		0.032
Mutation Taster		=95/5	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

hg19: chr12-108985478;