17-28367840-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000638.4(VTN):c.1199C>T(p.Thr400Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,613,858 control chromosomes in the GnomAD database, including 196,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20437 hom., cov: 33)
  • Exomes 𝑓: 0.49 (175631 hom.)
• Consequence: VTN NM_000638.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.85

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.3920254E-6).
• BP6: Variant 17-28367840-G-A is Benign according to our data. Variant chr17-28367840-G-A is described in ClinVar as [Benign]. Clinvar id is 3059155.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-28367840-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VTN	NM_000638.4	c.1199C>T	p.Thr400Met	missense_variant	7/8	ENST00000226218.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VTN	ENST00000226218.9	c.1199C>T	p.Thr400Met	missense_variant	7/8	1	NM_000638.4	P1
SARM1	ENST00000379061.8	n.170+2675G>A		intron_variant, non_coding_transcript_variant		2
VTN	ENST00000539746.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78324 AN: 152040 Hom.: 20437 Cov.: 33

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.524

GnomAD3 exomes AF: 0.509 AC: 126472 AN: 248412 Hom.: 32939 AF XY: 0.503 AC XY: 67694 AN XY: 134566

Gnomad AFR exome AF: 0.572

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.726

Gnomad SAS exome AF: 0.477

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.487 AC: 711439 AN: 1461700 Hom.: 175631 Cov.: 67 AF XY: 0.486 AC XY: 353139 AN XY: 727148

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.570

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.747

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.416

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.515 AC: 78355 AN: 152158 Hom.: 20437 Cov.: 33 AF XY: 0.513 AC XY: 38131 AN XY: 74390

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.723

Gnomad4 SAS AF: 0.470

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.520

Alfa AF: 0.489 Hom.: 21175

Bravo AF: 0.533

TwinsUK AF: 0.477 AC: 1768

ALSPAC AF: 0.450 AC: 1736

ESP6500AA AF: 0.566 AC: 2493

ESP6500EA AF: 0.481 AC: 4134

ExAC AF: 0.507 AC: 61511

Asia WGS AF: 0.525 AC: 1828 AN: 3478

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

Oct 30, 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
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.0060
Dann	Benign	0.97
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0000044	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.10	T;T
Polyphen		0.94	.;P
Vest4		0.053
MPC		0.22
ClinPred		0.023	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs704; hg19: chr17-26694861; COSMIC: COSV52647729; COSMIC: COSV52647729;