16-67228868-C-G

Variant names:

• chr16-67228868-C-G
• rs918067548
• NM_014187.4:c.371C>G

Variant summary

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

The NM_014187.4(TMEM208):​c.371C>G​(p.Ser124Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S124F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM208 NM_014187.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31295758).

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.371C>G	p.Ser124Cys	missense	Exon 5 of 6	NP_054906.2	Q9BTX3-1
	TMEM208	NM_001318217.2		c.161C>G	p.Ser54Cys	missense	Exon 5 of 6	NP_001305146.1	J3KRY7
	TMEM208	NR_134524.2		n.486C>G		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM208	ENST00000304800.14	TSL:1 MANE Select	c.371C>G	p.Ser124Cys	missense	Exon 5 of 6	ENSP00000305892.9	Q9BTX3-1
	TMEM208	ENST00000565201.1	TSL:2	c.371C>G	p.Ser124Cys	missense	Exon 5 of 5	ENSP00000454579.1	H3BMW4
	TMEM208	ENST00000563953.5	TSL:2	c.161C>G	p.Ser54Cys	missense	Exon 5 of 6	ENSP00000462217.1	J3KRY7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D
Sift4G	Benign	0.13	T
Polyphen		0.91	P
Vest4		0.39
MutPred		0.65		Gain of catalytic residue at S124 (P = 0.2481)
MVP		0.13
MPC		0.55
ClinPred		0.62	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs918067548; hg19: chr16-67262771;