chr12-108591875-C-T

Variant names:

• chr12-108591875-C-T
• rs201913296
• NM_181724.3:c.509G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_181724.3(TMEM119):​c.509G>A​(p.Arg170Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,609,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TMEM119 NM_181724.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.763
• Publications: 2 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010635167).
• BP6: Variant 12-108591875-C-T is Benign according to our data. Variant chr12-108591875-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2567944.Status of the report is criteria_provided_single_submitter, 1 stars.

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.509G>A	p.Arg170Gln	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.509G>A	p.Arg170Gln	missense	Exon 2 of 2	ENSP00000376553.3	Q4V9L6
	TMEM119	ENST00000861158.1		c.509G>A	p.Arg170Gln	missense	Exon 3 of 3	ENSP00000531217.1
	TMEM119	ENST00000861159.1		c.509G>A	p.Arg170Gln	missense	Exon 3 of 3	ENSP00000531218.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 8 AN: 245014 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000633

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1457758 Hom.: 0 Cov.: 30 AF XY: 0.000130 AC XY: 94 AN XY: 724924

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.0000449 AC: 2 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.000148 AC: 164 AN: 1110424

Other (OTH) AF: 0.000116 AC: 7 AN: 60186

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000840 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.061
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.76
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.036
Sift	Benign	0.86	T
Sift4G	Benign	0.46	T
Polyphen		0.043	B
Vest4		0.067
MutPred		0.15		Loss of MoRF binding (P = 0.0764)
MVP		0.23
MPC		0.15
ClinPred		0.043	T
GERP RS		0.11
Varity_R		0.029
gMVP		0.038
Mutation Taster		=96/4	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: rs201913296; hg19: chr12-108985651; COSMIC: COSV67189383; COSMIC: COSV67189383;