Variant 16-67228356-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014187.4(TMEM208):c.104C>T(p.Ala35Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM208
NM_014187.4 missense, splice_region

Scores

Splicing: ADA: 0.9140

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Variant links:

Genes affected

TMEM208 (HGNC:25015): (transmembrane protein 208) This gene encodes a highly conserved protein which is localized in the endoplasmic reticulum (ER). The protein is linked to autophagy and ER stress. Knockdown of this gene increased autophagy and triggered ER stress. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

TMEM208 links:

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ACMG classification

Classification made for transcript

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=0.20600423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM208	NM_014187.4 link	c.104C>T	p.Ala35Val	missense_variant, splice_region_variant	3/6	ENST00000304800.14	NP_054906.2	Q9BTX3-1
TMEM208	NM_001318217.2 link	c.-107C>T		splice_region_variant	3/6		NP_001305146.1	Q9BTX3J3KRY7
TMEM208	NM_001318217.2 link	c.-107C>T		5_prime_UTR_variant	3/6		NP_001305146.1	Q9BTX3J3KRY7
TMEM208	NR_134524.2 link	n.193C>T		splice_region_variant, non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM208	ENST00000304800.14 link	c.104C>T	p.Ala35Val	missense_variant, splice_region_variant	3/6	1	NM_014187.4	ENSP00000305892.9		Q9BTX3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727130

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2023

The c.104C>T (p.A35V) alteration is located in exon 3 (coding exon 3) of the TMEM208 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the alanine (A) at amino acid position 35 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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

T;T

Eigen

Benign

-0.081

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

L;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.088

Sift

Benign

0.19

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.12

B;.

Vest4

0.34

MutPred

0.54

Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);

MVP

0.048

MPC

0.21

ClinPred

0.29

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.73

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