12-111938197-G-C

Variant names:

• chr12-111938197-G-C
• NM_001193531.2:c.329C>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.329C>G​(p.Thr110Ser) 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. 15/22 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: TMEM116 NM_001193531.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• 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=0.104144424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM116	NM_001193531.2	c.329C>G	p.Thr110Ser	missense_variant	Exon 6 of 11	ENST00000552374.7	NP_001180460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM116	ENST00000552374.7	c.329C>G	p.Thr110Ser	missense_variant	Exon 6 of 11	1	NM_001193531.2	ENSP00000447731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329C>G (p.T110S) alteration is located in exon 6 (coding exon 5) of the TMEM116 gene. This alteration results from a C to G substitution at nucleotide position 329, causing the threonine (T) at amino acid position 110 to be replaced by a serine (S). 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	Benign	0.098
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0098	T;.;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.51	T;T;T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;.;.;.
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N;N;.;N
REVEL	Benign	0.0080
Sift	Benign	0.057	T;T;T;.;T
Sift4G	Uncertain	0.059	T;D;T;D;D
Polyphen		0.041	B;.;.;.;B
Vest4		0.14
MutPred		0.33		Gain of catalytic residue at R20 (P = 0.0041);.;.;Gain of catalytic residue at R20 (P = 0.0041);.;
MVP		0.30
MPC		0.14
ClinPred		0.22	T
GERP RS		2.7
Varity_R		0.079
gMVP		0.22
Mutation Taster		=296/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: chr12-112376001;