9-110375437-C-G

Variant names:

• chr9-110375437-C-G
• rs555132455
• NM_153366.4:c.10531G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153366.4(SVEP1):​c.10531G>C​(p.Gly3511Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000543 in 1,289,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: SVEP1 NM_153366.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

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>C	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>C	p.Gly3511Arg	missense	Exon 46 of 48	ENSP00000363593.2	Q4LDE5-1

Frequencies

GnomAD3 genomes AF: 0.00000784 AC: 1 AN: 127582 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000649 AC: 1 AN: 154138 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000516 AC: 6 AN: 1161884 Hom.: 0 Cov.: 36 AF XY: 0.00000519 AC XY: 3 AN XY: 577628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28990

American (AMR) AF: 0.00 AC: 0 AN: 34016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21364

East Asian (EAS) AF: 0.00 AC: 0 AN: 32692

South Asian (SAS) AF: 0.0000802 AC: 6 AN: 74854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4984

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 872486

Other (OTH) AF: 0.00 AC: 0 AN: 48606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00197931), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000783 AC: 1 AN: 127698 Hom.: 0 Cov.: 23 AF XY: 0.0000169 AC XY: 1 AN XY: 59338

African (AFR) AF: 0.00 AC: 0 AN: 34464

American (AMR) AF: 0.00 AC: 0 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4342

South Asian (SAS) AF: 0.000270 AC: 1 AN: 3702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 156

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63122

Other (OTH) AF: 0.00 AC: 0 AN: 1684

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.6
PrimateAI	Uncertain	0.71	T
REVEL	Uncertain	0.62
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.90		Loss of catalytic residue at C3514 (P = 0.1223)
MVP		0.12
MPC		0.52
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.54
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs555132455; hg19: chr9-113137717;