Genetic Variant TMED10:c.539-28T>C (chr14-75135034-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.343

Publications

22 publications found

Variant links:

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]

TMED10 links:

ENSG00000259138 (HGNC:):

ENSG00000259138 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.485

AC XY:

352498

AN XY:

726198

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16554

33108

49663

66217

82771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15736

31472

47208

62944

78680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.433

AC:

65862

AN:

152040

Hom.:

15964

Cov.:

AF XY:

0.438

AC XY:

32547

AN XY:

74308

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1766

3532

5298

7064

8830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.2

(source)

DANN

Benign

0.53

PhyloP100

0.34

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over