11-61392642-G-A

Position:

chr11-61392642-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001173990.3(TMEM216):c.11G>A(p.Arg4Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 1,513,934 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TMEM216
NM_001173990.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.39

Variant links:

Genes affected

TMEM216 (HGNC:25018): (transmembrane protein 216) This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

TMEM216 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Transmembrane protein 216 (size 144) in uniprot entity TM216_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001173990.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15406898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM216	NM_001173990.3 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	1/5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	1/5		NP_001167462.1
TMEM216	NM_001330285.2 linkuse as main transcript	c.-187G>A		5_prime_UTR_variant	1/5		NP_001317214.1
TMEM216	NM_016499.6 linkuse as main transcript	c.-187G>A		5_prime_UTR_variant	1/5		NP_057583.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7 linkuse as main transcript	c.11G>A	p.Arg4Gln	missense_variant	1/5	2	NM_001173990.3	ENSP00000440638	P4	Q9P0N5-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1362038

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

672730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000160

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151896

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.11G>A (p.R4Q) alteration is located in exon 1 (coding exon 1) of the TMEM216 gene. This alteration results from a G to A substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial aplasia of the vermis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4 of the TMEM216 protein (p.Arg4Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMEM216-related conditions. ClinVar contains an entry for this variant (Variation ID: 855127). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Joubert syndrome 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

0.037

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.56

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.20

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.38

T;T

Sift4G

Benign

0.46

T;T

Vest4

0.29

MutPred

0.20

Loss of MoRF binding (P = 0.0017);Loss of MoRF binding (P = 0.0017);

MVP

0.70

MPC

0.15

ClinPred

0.86

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.19

gMVP

0.21

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