12-108591971-A-G

Variant names:

• chr12-108591971-A-G
• NM_181724.3:c.413T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181724.3(TMEM119):​c.413T>C​(p.Val138Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V138M) has been classified 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: 8.58

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM119	NM_181724.3	c.413T>C	p.Val138Ala	missense_variant	Exon 2 of 2	ENST00000392806.4	NP_859075.2
TMEM119	XM_011538271.3	c.413T>C	p.Val138Ala	missense_variant	Exon 3 of 3		XP_011536573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM119	ENST00000392806.4	c.413T>C	p.Val138Ala	missense_variant	Exon 2 of 2	1	NM_181724.3	ENSP00000376553.3
TMEM119	ENST00000549031.1	c.413T>C	p.Val138Ala	missense_variant	Exon 3 of 3	4		ENSP00000448583.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413T>C (p.V138A) alteration is located in exon 2 (coding exon 1) of the TMEM119 gene. This alteration results from a T to C substitution at nucleotide position 413, causing the valine (V) at amino acid position 138 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.24		Loss of stability (P = 0.0427);Loss of stability (P = 0.0427);
MVP		0.58
MPC		0.65
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-108985747;