rs141194056

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-79311418-G-A
• chr15-79311418-G-T

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
• Publications: 5 publications found

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 VariationId is 2645626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007364.4. 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
	TMED3	NM_007364.4	MANE Select	c.168+1G>A		splice_donor intron	N/A	NP_031390.1	A0A140VKD1
	TMED3	NM_001330376.2		c.168+1G>A		splice_donor intron	N/A	NP_001317305.1	Q9Y3Q3-2
	TMED3	NM_001301203.3		c.168+1G>A		splice_donor intron	N/A	NP_001288132.1	F5H4M7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED3	ENST00000299705.10	TSL:1 MANE Select	c.168+1G>A		splice_donor intron	N/A	ENSP00000299705.5	Q9Y3Q3-1
	TMED3	ENST00000964020.1		c.168+1G>A		splice_donor intron	N/A	ENSP00000634079.1
	TMED3	ENST00000424155.6	TSL:3	c.168+1G>A		splice_donor intron	N/A	ENSP00000414983.2	Q9Y3Q3-2

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

African (AFR) AF: 0.000332 AC: 11 AN: 33138

American (AMR) AF: 0.000972 AC: 43 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00503 AC: 130 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.000720 AC: 61 AN: 84682

European-Finnish (FIN) AF: 0.00689 AC: 360 AN: 52280

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5560

European-Non Finnish (NFE) AF: 0.00412 AC: 4565 AN: 1107750

Other (OTH) 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

African (AFR) AF: 0.000601 AC: 25 AN: 41570

American (AMR) AF: 0.00131 AC: 20 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5128

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00980 AC: 104 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.1
GERP RS		4.7
PromoterAI		-0.27	Neutral
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

Other links and lift over

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