chr15-79311418-G-A

Variant names:

• chr15-79311418-G-A
• rs141194056
• NM_007364.4:c.168+1G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The NM_007364.4(TMED3):​c.168+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,604,818 control chromosomes in the GnomAD database, including 21 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: TMED3 NM_007364.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.09

Genes affected

TMED3 (HGNC:28889): (transmembrane p24 trafficking protein 3) Predicted to be involved in Golgi organization; endoplasmic reticulum to Golgi vesicle-mediated transport; and intracellular protein transport. Located in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.4678899 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 15-79311418-G-A is Benign according to our data. Variant chr15-79311418-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2645626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMED3	NM_007364.4	c.168+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	ENST00000299705.10	NP_031390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMED3	ENST00000299705.10	c.168+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_007364.4	ENSP00000299705.5
TMED3	ENST00000424155.6	c.168+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	3		ENSP00000414983.2
TMED3	ENST00000536821.5	c.168+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	2		ENSP00000446062.1
TMED3	ENST00000543455.1	n.168+1G>A		splice_donor_variant, intron_variant	Intron 1 of 3	2		ENSP00000440228.1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152116 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00319 AC: 740 AN: 231840 AF XY: 0.00304

Gnomad AFR exome AF: 0.000421

Gnomad AMR exome AF: 0.000952

Gnomad ASJ exome AF: 0.00472

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00790

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00369 AC: 5353 AN: 1452584 Hom.: 17 Cov.: 32 AF XY: 0.00371 AC XY: 2676 AN XY: 721626

Gnomad4 AFR exome AF: 0.000332 AC: 11 AN: 33138

Gnomad4 AMR exome AF: 0.000972 AC: 43 AN: 44234

Gnomad4 ASJ exome AF: 0.00503 AC: 130 AN: 25844

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39180

Gnomad4 SAS exome AF: 0.000720 AC: 61 AN: 84682

Gnomad4 FIN exome AF: 0.00689 AC: 360 AN: 52280

Gnomad4 NFE exome AF: 0.00412 AC: 4565 AN: 1107750

Gnomad4 Remaining exome AF: 0.00302 AC: 181 AN: 59916

GnomAD4 genome AF: 0.00372 AC: 567 AN: 152234 Hom.: 4 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74428

Gnomad4 AFR AF: 0.000601 AC: 0.000601395 AN: 0.000601395

Gnomad4 AMR AF: 0.00131 AC: 0.00130634 AN: 0.00130634

Gnomad4 ASJ AF: 0.00634 AC: 0.00634006 AN: 0.00634006

Gnomad4 EAS AF: 0.000195 AC: 0.000195008 AN: 0.000195008

Gnomad4 SAS AF: 0.000830 AC: 0.000829876 AN: 0.000829876

Gnomad4 FIN AF: 0.00980 AC: 0.00979838 AN: 0.00979838

Gnomad4 NFE AF: 0.00509 AC: 0.00508794 AN: 0.00508794

Gnomad4 OTH AF: 0.00189 AC: 0.00189394 AN: 0.00189394

Alfa AF: 0.00406 Hom.: 5

Bravo AF: 0.00308

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00443 AC: 38

ExAC AF: 0.00286 AC: 346

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMED3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		4.7
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 45
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141194056; hg19: chr15-79603760; COSMIC: COSV105170057; COSMIC: COSV105170057;