Genetic Variant TMED8:p.Ser2Pro (chr14-77377050-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_213601.3(TMED8):c.4T>C(p.Ser2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,366,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S2A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

TMED8
NM_213601.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

0 publications found

Variant links:

Genes affected

TMED8 (HGNC:18633): (transmembrane p24 trafficking protein family member 8)

TMED8 links:

SAMD15 (HGNC:18631): (sterile alpha motif domain containing 15)

SAMD15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213601.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMED8	NM_213601.3	MANE Select	c.4T>C	p.Ser2Pro	missense	Exon 1 of 6	NP_998766.1	Q6PL24
TMED8	NM_001346131.2		c.4T>C	p.Ser2Pro	missense	Exon 1 of 6	NP_001333060.1
TMED8	NM_001346133.2		c.-203T>C		5_prime_UTR	Exon 1 of 6	NP_001333062.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMED8	ENST00000216468.8	TSL:1 MANE Select	c.4T>C	p.Ser2Pro	missense	Exon 1 of 6	ENSP00000216468.7	Q6PL24
TMED8	ENST00000868372.1		c.4T>C	p.Ser2Pro	missense	Exon 1 of 6	ENSP00000538432.1
SAMD15	ENST00000533095.2	TSL:5	c.-70+310A>G		intron	N/A	ENSP00000450941.1	G3V2Z3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.24e-7

AC:

AN:

1214016

Hom.:

Cov.:

AF XY:

0.00000170

AC XY:

AN XY:

588762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23530

American (AMR)

AF:

0.00

AC:

AN:

11828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17028

East Asian (EAS)

AF:

0.00

AC:

AN:

28050

South Asian (SAS)

AF:

0.00

AC:

AN:

52858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

998532

Other (OTH)

AF:

0.0000200

AC:

AN:

49894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.35

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.2

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.25

MutPred

0.20

Gain of catalytic residue at S2 (P = 5e-04)

MVP

0.51

MPC

0.98

ClinPred

0.96

GERP RS

3.9

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.46

gMVP

0.15

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over