Genetic Variant SVEP1:p.Gln581His (chr9-110496872-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153366.4(SVEP1):c.1743A>T(p.Gln581His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SVEP1
NM_153366.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00200

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17433715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVEP1	NM_153366.4 link	c.1743A>T	p.Gln581His	missense_variant	Exon 8 of 48	ENST00000374469.6	NP_699197.3	Q4LDE5-1Q5JB40B3KQM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SVEP1	ENST00000374469.6 link	c.1743A>T	p.Gln581His	missense_variant	Exon 8 of 48	5	NM_153366.4	ENSP00000363593.2	Q4LDE5-1
SVEP1	ENST00000374461.1 link	c.1743A>T	p.Gln581His	missense_variant	Exon 8 of 14	1		ENSP00000363585.2	Q4LDE5-2
SVEP1	ENST00000467821.1 link	n.1162A>T		non_coding_transcript_exon_variant	Exon 7 of 26	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1406084

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32284

American (AMR)

AF:

0.00

AC:

AN:

36342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

36992

South Asian (SAS)

AF:

0.00

AC:

AN:

79718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081642

Other (OTH)

AF:

0.00

AC:

AN:

58286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

3752

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

T;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.5

.;M;M

PhyloP100

-0.0020

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.0

D;.;.

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;.;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0, 0.028

.;D;B

Vest4

0.055

MutPred

0.23

Loss of catalytic residue at Q581 (P = 0.0581);Loss of catalytic residue at Q581 (P = 0.0581);Loss of catalytic residue at Q581 (P = 0.0581);

MVP

0.23

MPC

0.096

ClinPred

0.97

GERP RS

0.97

Varity_R

0.49

gMVP

0.33

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over