Genetic Variant TMEM119:p.Tyr128His (chr12-108592002-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_181724.3(TMEM119):c.382T>C(p.Tyr128His) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMEM119
NM_181724.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.80

Variant links:

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]

TMEM119 links:

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ACMG classification

Classification made for transcript

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 link	c.382T>C	p.Tyr128His	missense_variant	Exon 2 of 2	ENST00000392806.4	NP_859075.2	Q4V9L6
TMEM119	XM_011538271.3 link	c.382T>C	p.Tyr128His	missense_variant	Exon 3 of 3		XP_011536573.1	Q4V9L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM119	ENST00000392806.4 link	c.382T>C	p.Tyr128His	missense_variant	Exon 2 of 2	1	NM_181724.3	ENSP00000376553.3	Q4V9L6
TMEM119	ENST00000549031.1 link	c.382T>C	p.Tyr128His	missense_variant	Exon 3 of 3	4		ENSP00000448583.1	F8VS22
TMEM119	ENST00000549447.1 link	c.*250T>C		downstream_gene_variant		4		ENSP00000447120.1	F8W0W9

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000580

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382T>C (p.Y128H) 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 382, causing the tyrosine (Y) at amino acid position 128 to be replaced by a histidine (H). 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

0.80

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.54

MVP

0.40

MPC

0.67

ClinPred

1.0

GERP RS

4.5

Varity_R

0.82

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over