Genetic Variant NM_153366.4:c.5429A>C (chr9-110430375-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_153366.4(SVEP1):c.5429A>C(p.Glu1810Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,612,688 control chromosomes in the GnomAD database, including 28,542 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1810K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 2264 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26278 hom. )

Consequence

SVEP1
NM_153366.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

19 publications found

Variant links:

Genes affected

SVEP1 (HGNC:15985): (sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1) Predicted to enable calcium ion binding activity and chromatin binding activity. Predicted to be involved in epidermis development and lymph vessel morphogenesis. Predicted to act upstream of or within several processes, including Tie signaling pathway; lymph circulation; and lymph vessel development. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SVEP1 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=0.019336492).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVEP1	NM_153366.4 link	c.5429A>C	p.Glu1810Ala	missense_variant	Exon 33 of 48	ENST00000374469.6	NP_699197.3	Q4LDE5-1Q5JB40B3KQM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVEP1	ENST00000374469.6 link	c.5429A>C	p.Glu1810Ala	missense_variant	Exon 33 of 48	5	NM_153366.4	ENSP00000363593.2		Q4LDE5-1

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22674

AN:

151984

Hom.:

2255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.157

GnomAD2 exomes

AF:

0.204

AC:

50527

AN:

247354

AF XY:

0.199

show subpopulations

Gnomad AFR exome

AF:

0.0313

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.180

AC:

263454

AN:

1460586

Hom.:

26278

Cov.:

AF XY:

0.179

AC XY:

130027

AN XY:

726466

show subpopulations

African (AFR)

AF:

0.0286

AC:

957

AN:

33464

American (AMR)

AF:

0.283

AC:

12602

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

3596

AN:

26110

East Asian (EAS)

AF:

0.419

AC:

16641

AN:

39688

South Asian (SAS)

AF:

0.163

AC:

13996

AN:

86116

European-Finnish (FIN)

AF:

0.247

AC:

13167

AN:

53304

Middle Eastern (MID)

AF:

0.162

AC:

932

AN:

5760

European-Non Finnish (NFE)

AF:

0.172

AC:

191240

AN:

1111328

Other (OTH)

AF:

0.171

AC:

10323

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

10835

21671

32506

43342

54177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6832

13664

20496

27328

34160

<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:

0.149

AC:

22696

AN:

152102

Hom.:

2264

Cov.:

AF XY:

0.156

AC XY:

11567

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0339

AC:

1407

AN:

41546

American (AMR)

AF:

0.206

AC:

3141

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

462

AN:

3472

East Asian (EAS)

AF:

0.426

AC:

2192

AN:

5148

South Asian (SAS)

AF:

0.172

AC:

828

AN:

4820

European-Finnish (FIN)

AF:

0.248

AC:

2614

AN:

10560

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11602

AN:

67970

Other (OTH)

AF:

0.161

AC:

340

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

925

1849

2774

3698

4623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.169

Hom.:

5767

Bravo

AF:

0.148

TwinsUK

AF:

0.175

AC:

650

ALSPAC

AF:

0.172

AC:

661

ESP6500AA

AF:

0.0365

AC:

137

ESP6500EA

AF:

0.170

AC:

1400

ExAC

AF:

0.197

AC:

23774

Asia WGS

AF:

0.247

AC:

859

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.65

.;N

PhyloP100

2.3

PrimateAI

Benign

0.27

REVEL

Benign

0.090

Sift4G

Benign

0.092

T;T

Polyphen

0.0040

.;B

Vest4

0.071

MPC

0.10

ClinPred

0.0060

GERP RS

2.8

Varity_R

0.11

gMVP

0.67

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over