17-28367462-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000638.4(VTN):c.1344T>C(p.Asn448=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,613,202 control chromosomes in the GnomAD database, including 8,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1111 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6901 hom.)
• Consequence: VTN NM_000638.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.99

Genes affected

VTN (HGNC:12724): (vitronectin) The protein encoded by this gene functions in part as an adhesive glycoprotein. Differential expression of this protein can promote either cell adhesion or migration as it links cells to the extracellular matrix through a variety of ligands. These ligands include integrins, plasminogen activator inhibitor-1, and urokinase plasminogen activator receptor. This secreted protein can be present in the plasma as a monomer or dimer and forms a multimer in the extracellular matrix of several tissues. This protein also inhibits the membrane-damaging effect of the terminal cytolytic complement pathway and binds to several serpin serine protease inhibitors. This protein can also promote extracellular matrix degradation and thus plays a role in tumorigenesis. It is involved in a variety of other biological processes such as the regulation of the coagulation pathway, wound healing, and tissue remodeling. The heparin-binding domain of this protein give it anti-microbial properties. It is also a lipid binding protein that forms a principal component of high density lipoprotein. [provided by RefSeq, Aug 2020]

SARM1 (HGNC:17074): (sterile alpha and TIR motif containing 1) Enables NAD+ nucleotidase, cyclic ADP-ribose generating and identical protein binding activity. Involved in NAD catabolic process; positive regulation of neuron death; and response to axon injury. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-28367462-A-G is Benign according to our data. Variant chr17-28367462-A-G is described in ClinVar as [Benign]. Clinvar id is 3059030.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-28367462-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VTN	NM_000638.4	c.1344T>C	p.Asn448=	synonymous_variant	8/8	ENST00000226218.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VTN	ENST00000226218.9	c.1344T>C	p.Asn448=	synonymous_variant	8/8	1	NM_000638.4	P1
SARM1	ENST00000379061.8	n.170+2297A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16874 AN: 152044 Hom.: 1098 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0786

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.110 AC: 27448 AN: 250188 Hom.: 1814 AF XY: 0.111 AC XY: 15021 AN XY: 135434

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0898

Gnomad ASJ exome AF: 0.0756

Gnomad EAS exome AF: 0.233

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0807

Gnomad OTH exome AF: 0.0916

GnomAD4 exome AF: 0.0900 AC: 131562 AN: 1461040 Hom.: 6901 Cov.: 31 AF XY: 0.0922 AC XY: 66979 AN XY: 726844

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.0867

Gnomad4 ASJ exome AF: 0.0749

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0781

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.111 AC: 16923 AN: 152162 Hom.: 1111 Cov.: 32 AF XY: 0.113 AC XY: 8419 AN XY: 74386

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0786

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0800

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0871 Hom.: 778

Bravo AF: 0.110

Asia WGS AF: 0.233 AC: 808 AN: 3478

EpiCase AF: 0.0798

EpiControl AF: 0.0776

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

VTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.6
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2227728; hg19: chr17-26694483; COSMIC: COSV52647298; COSMIC: COSV52647298;