12-111991792-T-G

Variant names:

• chr12-111991792-T-G
• rs1465897840
• NM_001193531.2:c.176A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001193531.2(TMEM116):​c.176A>C​(p.Asp59Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,383,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D59V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM116 NM_001193531.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40251952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM116	NM_001193531.2	c.176A>C	p.Asp59Ala	missense_variant	Exon 4 of 11	ENST00000552374.7	NP_001180460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM116	ENST00000552374.7	c.176A>C	p.Asp59Ala	missense_variant	Exon 4 of 11	1	NM_001193531.2	ENSP00000447731.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383384 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 682666

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35694

South Asian (SAS) AF: 0.00 AC: 0 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078512

Other (OTH) AF: 0.0000173 AC: 1 AN: 57924

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.74	T
PhyloP100		4.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.020	D;D;D;D;D
Sift4G	Benign	0.068	T;D;D;.;.
Polyphen		1.0	.;.;D;.;.
Vest4		0.65
MutPred		0.45		Gain of catalytic residue at S54 (P = 0.0013);Gain of catalytic residue at S54 (P = 0.0013);Gain of catalytic residue at S54 (P = 0.0013);Gain of catalytic residue at S54 (P = 0.0013);Gain of catalytic residue at S54 (P = 0.0013);
MVP		0.39
MPC		0.69
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.31
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1465897840; hg19: chr12-112429596;