Genetic Variant SVEP1:p.Gly3511Arg (chr9-110375437-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_153366.4(SVEP1):c.10531G>A(p.Gly3511Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,289,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SVEP1
NM_153366.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153366.4. 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
	SVEP1	NM_153366.4	MANE Select	c.10531G>A	p.Gly3511Arg	missense	Exon 46 of 48	NP_699197.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SVEP1	ENST00000374469.6	TSL:5 MANE Select	c.10531G>A	p.Gly3511Arg	missense	Exon 46 of 48	ENSP00000363593.2	Q4LDE5-1

Frequencies

GnomAD3 genomes

AF:

0.0000392

AC:

AN:

127582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.0000475

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000195

AC:

AN:

154138

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1161884

Hom.:

Cov.:

AF XY:

0.0000242

AC XY:

AN XY:

577628

show subpopulations

African (AFR)

AF:

0.000103

AC:

AN:

28990

American (AMR)

AF:

0.0000294

AC:

AN:

34016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21364

East Asian (EAS)

AF:

0.00

AC:

AN:

32692

South Asian (SAS)

AF:

0.0000534

AC:

AN:

74854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4984

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

872486

Other (OTH)

AF:

0.0000411

AC:

AN:

48606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000392

AC:

AN:

127582

Hom.:

Cov.:

AF XY:

0.0000338

AC XY:

AN XY:

59238

show subpopulations

African (AFR)

AF:

0.0000291

AC:

AN:

34362

American (AMR)

AF:

0.0000947

AC:

AN:

10556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3316

East Asian (EAS)

AF:

0.00

AC:

AN:

4348

South Asian (SAS)

AF:

0.00

AC:

AN:

3716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.0000475

AC:

AN:

63124

Other (OTH)

AF:

0.00

AC:

AN:

1664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000480

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.1

PhyloP100

4.6

PrimateAI

Uncertain

0.71

REVEL

Uncertain

0.61

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.90

Loss of catalytic residue at C3514 (P = 0.1223)

MVP

0.12

MPC

0.52

ClinPred

0.99

GERP RS

5.6

Varity_R

0.51

gMVP

0.54

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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