Genetic Variant NM_181836.6:c.570A>T (chr5-115616314-T-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3BP6_ModerateBS1BS2

The NM_181836.6(TMED7):c.570A>T(p.Ser190Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,614,188 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S190S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 33)

Exomes 𝑓: 0.017 ( 270 hom. )

Consequence

TMED7
NM_181836.6 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.235

Publications

5 publications found

Variant links:

Genes affected

TMED7 (HGNC:24253): (transmembrane p24 trafficking protein 7) 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]

TMED7 links:

TMED7-TICAM2 (HGNC:33945): (TMED7-TICAM2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring transmembrane emp24 protein transport domain containing 7 (TMED7) and toll-like receptor adaptor molecule 2 (TICAM2) genes. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. This fusion product functions to negatively regulate the adaptor MyD88-independent toll-like receptor 4 pathway. [provided by RefSeq, Nov 2010]

TMED7-TICAM2 links:

TICAM2-AS1 (HGNC:55575): (TICAM2 antisense RNA 1)

TICAM2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 5-115616314-T-A is Benign according to our data. Variant chr5-115616314-T-A is described in ClinVar as Benign. ClinVar VariationId is 1657409.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1931/152342) while in subpopulation NFE AF = 0.0166 (1132/68018). AF 95% confidence interval is 0.0158. There are 19 homozygotes in GnomAd4. There are 920 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181836.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMED7	NM_181836.6	MANE Select	c.570A>T	p.Ser190Ser	synonymous	Exon 3 of 3	NP_861974.1	Q9Y3B3-1
TMED7-TICAM2	NM_001164468.4		c.566+4A>T		splice_region intron	N/A	NP_001157940.1
TMED7-TICAM2	NM_001164469.4		c.566+4A>T		splice_region intron	N/A	NP_001157941.1	A0A0A6YYA0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMED7	ENST00000456936.4	TSL:1 MANE Select	c.570A>T	p.Ser190Ser	synonymous	Exon 3 of 3	ENSP00000405926.3	Q9Y3B3-1
TMED7-TICAM2	ENST00000282382.8	TSL:2	c.566+4A>T		splice_region intron	N/A	ENSP00000282382.4
TMED7	ENST00000878959.1		c.570A>T	p.Ser190Ser	synonymous	Exon 4 of 4	ENSP00000549018.1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1932

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0593

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0144

AC:

3588

AN:

249374

AF XY:

0.0148

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00989

Gnomad ASJ exome

AF:

0.0525

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0169

AC:

24674

AN:

1461846

Hom.:

270

Cov.:

AF XY:

0.0168

AC XY:

12223

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

33478

American (AMR)

AF:

0.0106

AC:

476

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

1370

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00691

AC:

596

AN:

86258

European-Finnish (FIN)

AF:

0.0165

AC:

879

AN:

53420

Middle Eastern (MID)

AF:

0.0321

AC:

185

AN:

5768

European-Non Finnish (NFE)

AF:

0.0180

AC:

20021

AN:

1111980

Other (OTH)

AF:

0.0175

AC:

1054

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1613

3227

4840

6454

8067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.0127

AC:

1931

AN:

152342

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

920

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00320

AC:

133

AN:

41596

American (AMR)

AF:

0.0145

AC:

222

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0593

AC:

206

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0104

AC:

110

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0166

AC:

1132

AN:

68018

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0202

Hom.:

Bravo

AF:

0.0134

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0184

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.6

(source)

DANN

Benign

0.86

PhyloP100

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=40/60

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -42

DS_DL_spliceai

0.58

Position offset: 4

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