14-77377050-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

Genes affected

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

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3191206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMED8	NM_213601.3	c.4T>G	p.Ser2Ala	missense_variant	1/6	ENST00000216468.8
TMED8	NM_001346131.2	c.4T>G	p.Ser2Ala	missense_variant	1/6
TMED8	NM_001346133.2	c.-203T>G		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMED8	ENST00000216468.8	c.4T>G	p.Ser2Ala	missense_variant	1/6	1	NM_213601.3	P1
SAMD15	ENST00000533095.2	c.-70+310A>C		intron_variant		5

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000200

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

The c.4T>G (p.S2A) alteration is located in exon 1 (coding exon 1) of the TMED8 gene. This alteration results from a T to G substitution at nucleotide position 4, causing the serine (S) at amino acid position 2 to be replaced by an alanine (A). 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	0.097
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
MutationTaster	Benign	1.0	D;N
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
Varity_R		0.32
gMVP		0.091

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

LitVar

Other links and lift over

dbSNP: rs1893838474; hg19: chr14-77843393;