dbSNP rs1976165: SEZ6:p.Thr546Ala (chr17-28959833-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_178860.5(SEZ6):c.1636A>G(p.Thr546Ala) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,613,136 control chromosomes in the GnomAD database, including 61,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 8366 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53183 hom. )

Consequence

SEZ6
NM_178860.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.86

Publications

33 publications found

Variant links:

Genes affected

SEZ6 (HGNC:15955): (seizure related 6 homolog) The protein encoded by this gene is thought to contain five cysteine-rich motifs that are similar to sushi domains, as well as two domains similar to the amino terminal half of the CUB (for complement C1r/C1s, Uegf, Bmp1) domain. Mutations in this gene have been associated with febrile seizures. [provided by RefSeq, Jul 2016]

SEZ6 links:

PIPOX (HGNC:17804): (pipecolic acid and sarcosine oxidase) Enables L-pipecolate oxidase activity and sarcosine oxidase activity. Involved in L-lysine catabolic process to acetyl-CoA via L-pipecolate. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

PIPOX links:

LOC105371716 (HGNC:):

LOC105371716 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002216816).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEZ6	NM_178860.5 link	c.1636A>G	p.Thr546Ala	missense_variant	Exon 8 of 17	ENST00000317338.17	NP_849191.3	Q53EL9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEZ6	ENST00000317338.17 link	c.1636A>G	p.Thr546Ala	missense_variant	Exon 8 of 17	1	NM_178860.5	ENSP00000312942.11		Q53EL9-1

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48194

AN:

151970

Hom.:

8360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.300

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.327

GnomAD2 exomes

AF:

0.283

AC:

70036

AN:

247794

AF XY:

0.284

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.265

AC:

387339

AN:

1461046

Hom.:

53183

Cov.:

AF XY:

0.267

AC XY:

194316

AN XY:

726752

show subpopulations

African (AFR)

AF:

0.469

AC:

15699

AN:

33472

American (AMR)

AF:

0.268

AC:

11939

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

7041

AN:

26106

East Asian (EAS)

AF:

0.248

AC:

9842

AN:

39694

South Asian (SAS)

AF:

0.363

AC:

31262

AN:

86172

European-Finnish (FIN)

AF:

0.264

AC:

14062

AN:

53362

Middle Eastern (MID)

AF:

0.311

AC:

1789

AN:

5748

European-Non Finnish (NFE)

AF:

0.250

AC:

278333

AN:

1111534

Other (OTH)

AF:

0.288

AC:

17372

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16191

32383

48574

64766

80957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9652

19304

28956

38608

48260

<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:

0.317

AC:

48231

AN:

152090

Hom.:

8366

Cov.:

AF XY:

0.317

AC XY:

23575

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.460

AC:

19053

AN:

41436

American (AMR)

AF:

0.300

AC:

4589

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

960

AN:

3466

East Asian (EAS)

AF:

0.239

AC:

1237

AN:

5174

South Asian (SAS)

AF:

0.364

AC:

1754

AN:

4820

European-Finnish (FIN)

AF:

0.266

AC:

2814

AN:

10588

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16837

AN:

67994

Other (OTH)

AF:

0.324

AC:

685

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1660

3320

4980

6640

8300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.274

Hom.:

19504

Bravo

AF:

0.326

TwinsUK

AF:

0.248

AC:

920

ALSPAC

AF:

0.253

AC:

975

ESP6500AA

AF:

0.429

AC:

1790

ESP6500EA

AF:

0.255

AC:

2162

ExAC

AF:

0.287

AC:

34741

Asia WGS

AF:

0.339

AC:

1182

AN:

3478

EpiCase

AF:

0.254

EpiControl

AF:

0.262

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0091

.;T;T;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.44

T;T;T;T;T

MetaRNN

Benign

0.0022

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.73

N;.;N;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.26

N;.;.;.;N

REVEL

Benign

0.079

Sift

Benign

0.31

T;.;.;.;T

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.033

MPC

0.26

ClinPred

0.0076

GERP RS

5.1

Varity_R

0.067

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over