NM_213601.3:c.4T>G

Variant names:

• chr14-77377050-A-C
• rs1893838474
• NM_213601.3:c.4T>G

Variant summary

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

The NM_213601.3(TMED8):​c.4T>G​(p.Ser2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,214,016 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TMED8 NM_213601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

Genes affected

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

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

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=0.3191206).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED8	NM_213601.3	MANE Select	c.4T>G	p.Ser2Ala	missense	Exon 1 of 6	NP_998766.1	Q6PL24
	TMED8	NM_001346131.2		c.4T>G	p.Ser2Ala	missense	Exon 1 of 6	NP_001333060.1
	TMED8	NM_001346133.2		c.-203T>G		5_prime_UTR	Exon 1 of 6	NP_001333062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED8	ENST00000216468.8	TSL:1 MANE Select	c.4T>G	p.Ser2Ala	missense	Exon 1 of 6	ENSP00000216468.7	Q6PL24
	TMED8	ENST00000868372.1		c.4T>G	p.Ser2Ala	missense	Exon 1 of 6	ENSP00000538432.1
	SAMD15	ENST00000533095.2	TSL:5	c.-70+310A>C		intron	N/A	ENSP00000450941.1	G3V2Z3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1214016 Hom.: 0 Cov.: 28 AF XY: 0.00000170 AC XY: 1 AN XY: 588762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23530

American (AMR) AF: 0.00 AC: 0 AN: 11828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17028

East Asian (EAS) AF: 0.00 AC: 0 AN: 28050

South Asian (SAS) AF: 0.00 AC: 0 AN: 52858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3436

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 998532

Other (OTH) AF: 0.00 AC: 0 AN: 49894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.097
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.019
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.24	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.059
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.43	B
Vest4		0.20
MutPred		0.14		Loss of phosphorylation at S2 (P = 0.0348)
MVP		0.43
MPC		0.78
ClinPred		0.95	D
GERP RS		3.9
PromoterAI		0.35	Neutral
Varity_R		0.32
gMVP		0.091
Mutation Taster		=89/11	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: rs1893838474; hg19: chr14-77843393;