14-75135008-T-TA

Position:

• chr14-75135008-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000303575.9(TMED10):​c.539-3_539-2insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,492,250 control chromosomes in the GnomAD database, including 11 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: TMED10 ENST00000303575.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.167

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 14-75135008-T-TA is Benign according to our data. Variant chr14-75135008-T-TA is described in ClinVar as [Benign]. Clinvar id is 786251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00603 (911/151050) while in subpopulation AFR AF= 0.0212 (870/41126). AF 95% confidence interval is 0.02. There are 8 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 911 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMED10	NM_006827.6	c.539-3_539-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000303575.9	NP_006818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMED10	ENST00000303575.9	c.539-3_539-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006827.6	ENSP00000303145	P1
	ENST00000556236.1	n.209-1755dup		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 911 AN: 150932 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00338

GnomAD4 exome AF: 0.00144 AC: 1938 AN: 1341200 Hom.: 3 Cov.: 31 AF XY: 0.00138 AC XY: 922 AN XY: 667110

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.00225

Gnomad4 ASJ exome AF: 0.00156

Gnomad4 EAS exome AF: 0.00155

Gnomad4 SAS exome AF: 0.000720

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.000764

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00603 AC: 911 AN: 151050 Hom.: 8 Cov.: 32 AF XY: 0.00568 AC XY: 419 AN XY: 73730

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00158

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00335

Alfa AF: 0.0141 Hom.: 0

Bravo AF: 0.00682

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs200389497; hg19: chr14-75601711;