chr9-110375437-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153366.4(SVEP1):​c.10531G>T​(p.Gly3511*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000861 in 1,161,884 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: SVEP1 NM_153366.4 stop_gained
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Gly3511*	stop_gained	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>T	p.Gly3511*	stop_gained	Exon 46 of 48	ENSP00000363593.2	Q4LDE5-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 8.61e-7 AC: 1 AN: 1161884 Hom.: 0 Cov.: 36 AF XY: 0.00000173 AC XY: 1 AN XY: 577628

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

African (AFR) AF: 0.0000345 AC: 1 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: 0.00 AC: 0 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.6
Vest4		0.45
GERP RS		5.6
Mutation Taster		=8/192	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;