12-111943321-A-C

Variant names:

• chr12-111943321-A-C
• ENST00000550831.7:c.-18T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193531.2(TMEM116):​c.259T>G​(p.Leu87Val) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM116 NM_001193531.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20
• Publications: 0 publications found

Genes affected

TMEM116 (HGNC:25084): (transmembrane protein 116) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20860052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM116	NM_001193531.2	c.259T>G	p.Leu87Val	missense_variant	Exon 5 of 11	ENST00000552374.7	NP_001180460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM116	ENST00000552374.7	c.259T>G	p.Leu87Val	missense_variant	Exon 5 of 11	1	NM_001193531.2	ENSP00000447731.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259T>G (p.L87V) alteration is located in exon 5 (coding exon 4) of the TMEM116 gene. This alteration results from a T to G substitution at nucleotide position 259, causing the leucine (L) at amino acid position 87 to be replaced by a valine (V). 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
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.90
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		1.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.47	T;T;T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.50
MutPred		0.32		Gain of catalytic residue at W85 (P = 0.004);Gain of catalytic residue at W85 (P = 0.004);Gain of catalytic residue at W85 (P = 0.004);
MVP		0.28
MPC		0.62
ClinPred		0.24	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.32
Mutation Taster		=79/21	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: chr12-112381125;