rs2986671

Variant names:

• chr9-110430375-T-G
• rs2986671
• NM_153366.4:c.5429A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 19 publications found

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]

ACMG classification

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	c.5429A>C	p.Glu1810Ala	missense_variant	Exon 33 of 48	ENST00000374469.6	NP_699197.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22674 AN: 151984 Hom.: 2255 Cov.: 32

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

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.: 33 AF XY: 0.179 AC XY: 130027 AN XY: 726466

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

GnomAD4 genome AF: 0.149 AC: 22696 AN: 152102 Hom.: 2264 Cov.: 32 AF XY: 0.156 AC XY: 11567 AN XY: 74334

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: 34 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11602 AN: 67970

Other (OTH) AF: 0.161 AC: 340 AN: 2108

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	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.65	.;N
PhyloP100		2.3
PrimateAI	Benign	0.27	T
REVEL	Benign	0.090
Sift4G	Benign	0.092	T;T
Polyphen		0.0040	.;B
Vest4		0.071
MPC		0.10
ClinPred		0.0060	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.67
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2986671; hg19: chr9-113192655; COSMIC: COSV52837027;