NM_006827.6:c.539-28T>C

Variant names:

• chr14-75135034-A-G
• rs12435391
• NM_006827.6:c.539-28T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006827.6(TMED10):​c.539-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,611,808 control chromosomes in the GnomAD database, including 194,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.43 (15964 hom., cov: 32)
  • Exomes 𝑓: 0.49 (178653 hom.)
• Consequence: TMED10 NM_006827.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.343
• Publications: 22 publications found

Genes affected

TMED10 (HGNC:16998): (transmembrane p24 trafficking protein 10) This gene is a member of the EMP24/GP25L/p24 family and encodes a protein with a GOLD domain. This type I membrane protein is localized to the plasma membrane and golgi cisternae and is involved in vesicular protein trafficking. The protein is also a member of a heteromeric secretase complex and regulates the complex's gamma-secretase activity without affecting its epsilon-secretase activity. Mutations in this gene have been associated with early-onset familial Alzheimer's disease. This gene has a pseudogene on chromosome 8. [provided by RefSeq, Jul 2008]

ENSG00000259138 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-75135034-A-G is Benign according to our data. Variant chr14-75135034-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006827.6. 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
	TMED10	NM_006827.6	MANE Select	c.539-28T>C		intron	N/A	NP_006818.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED10	ENST00000303575.9	TSL:1 MANE Select	c.539-28T>C		intron	N/A	ENSP00000303145.4	P49755
	TMED10	ENST00000555036.1	TSL:1	n.322-28T>C		intron	N/A
	TMED10	ENST00000555873.1	TSL:1	n.*175-28T>C		intron	N/A	ENSP00000450726.1	G3V2K7

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65830 AN: 151922 Hom.: 15955 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.521 AC: 130499 AN: 250586 AF XY: 0.512

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.487 AC: 710561 AN: 1459768 Hom.: 178653 Cov.: 37 AF XY: 0.485 AC XY: 352498 AN XY: 726198

African (AFR) AF: 0.218 AC: 7285 AN: 33346

American (AMR) AF: 0.706 AC: 31482 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12038 AN: 26090

East Asian (EAS) AF: 0.828 AC: 32844 AN: 39666

South Asian (SAS) AF: 0.444 AC: 38279 AN: 86124

European-Finnish (FIN) AF: 0.484 AC: 25749 AN: 53196

Middle Eastern (MID) AF: 0.438 AC: 2521 AN: 5762

European-Non Finnish (NFE) AF: 0.478 AC: 531238 AN: 1110688

Other (OTH) AF: 0.483 AC: 29125 AN: 60302

GnomAD4 genome AF: 0.433 AC: 65862 AN: 152040 Hom.: 15964 Cov.: 32 AF XY: 0.438 AC XY: 32547 AN XY: 74308

African (AFR) AF: 0.230 AC: 9564 AN: 41496

American (AMR) AF: 0.581 AC: 8872 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1608 AN: 3468

East Asian (EAS) AF: 0.836 AC: 4330 AN: 5180

South Asian (SAS) AF: 0.438 AC: 2107 AN: 4814

European-Finnish (FIN) AF: 0.491 AC: 5185 AN: 10554

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32732 AN: 67944

Other (OTH) AF: 0.444 AC: 938 AN: 2112

Alfa AF: 0.376 Hom.: 5544

Bravo AF: 0.436

Asia WGS AF: 0.568 AC: 1974 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.2
DANN	Benign	0.53
PhyloP100		0.34
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12435391; hg19: chr14-75601737; COSMIC: COSV57847624;