11-125097652-T-C

Position:

• chr11-125097652-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258244.2(TMEM218):​c.302A>G​(p.His101Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM218 NM_001258244.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

Genes affected

TMEM218 (HGNC:27344): (transmembrane protein 218) Predicted to be located in cilium. Predicted to be integral component of membrane. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM218 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17943004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM218	NM_001258244.2	c.302A>G	p.His101Arg	missense_variant	5/5	ENST00000682305.1	NP_001245173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM218	ENST00000682305.1	c.302A>G	p.His101Arg	missense_variant	5/5		NM_001258244.2	ENSP00000506979.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.302A>G (p.H101R) alteration is located in exon 4 (coding exon 3) of the TMEM218 gene. This alteration results from a A to G substitution at nucleotide position 302, causing the histidine (H) at amino acid position 101 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T;.;T;T;T;T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	.;T;.;.;.;.;.;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.;M;M;M;M;M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.11	T;T;T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T
Polyphen		0.18	B;P;B;B;B;B;B;B
Vest4		0.28
MutPred		0.41		.;Loss of sheet (P = 0.0142);.;.;.;.;.;.;
MVP		0.055
ClinPred		0.50	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.76

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: chr11-124967548;