rs374909823

Variant names:

• chr16-67229073-G-A
• rs374909823
• NM_014187.4:c.482G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014187.4(TMEM208):​c.482G>A​(p.Arg161Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,612,924 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TMEM208 NM_014187.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• Publications: 2 publications found

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]

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=0.10261351).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014187.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM208	NM_014187.4	MANE Select	c.482G>A	p.Arg161Gln	missense	Exon 6 of 6	NP_054906.2	Q9BTX3-1
	TMEM208	NM_001318217.2		c.272G>A	p.Arg91Gln	missense	Exon 6 of 6	NP_001305146.1	J3KRY7
	TMEM208	NR_134524.2		n.597G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM208	ENST00000304800.14	TSL:1 MANE Select	c.482G>A	p.Arg161Gln	missense	Exon 6 of 6	ENSP00000305892.9	Q9BTX3-1
	TMEM208	ENST00000563953.5	TSL:2	c.272G>A	p.Arg91Gln	missense	Exon 6 of 6	ENSP00000462217.1	J3KRY7
	TMEM208	ENST00000565201.1	TSL:2	c.*153G>A		3_prime_UTR	Exon 5 of 5	ENSP00000454579.1	H3BMW4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000605 AC: 15 AN: 247818 AF XY: 0.0000816

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1460592 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 726486

African (AFR) AF: 0.0000898 AC: 3 AN: 33412

American (AMR) AF: 0.0000449 AC: 2 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111314

Other (OTH) AF: 0.0000497 AC: 3 AN: 60304

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74480

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.065
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.24	T
Polyphen		0.47	P
Vest4		0.16
MVP		0.29
MPC		0.21
ClinPred		0.076	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.44
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs374909823; hg19: chr16-67262976; COSMIC: COSV99263884; COSMIC: COSV99263884;