17-28367869-G-A

Position:

• chr17-28367869-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000638.4(VTN):​c.1170C>T​(p.Asn390=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,026 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (98 hom.)
• Consequence: VTN NM_000638.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.644

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-28367869-G-A is Benign according to our data. Variant chr17-28367869-G-A is described in ClinVar as [Benign]. Clinvar id is 771493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.644 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VTN	NM_000638.4	c.1170C>T	p.Asn390=	synonymous_variant	7/8	ENST00000226218.9	NP_000629.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VTN	ENST00000226218.9	c.1170C>T	p.Asn390=	synonymous_variant	7/8	1	NM_000638.4	ENSP00000226218	P1
VTN	ENST00000539746.1	n.608C>T		non_coding_transcript_exon_variant	2/2	2
SARM1	ENST00000379061.8	n.170+2704G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 896 AN: 152224 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0446

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0228

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00920 AC: 2279 AN: 247780 Hom.: 63 AF XY: 0.00771 AC XY: 1036 AN XY: 134368

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0196

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.00641

GnomAD4 exome AF: 0.00260 AC: 3807 AN: 1461684 Hom.: 98 Cov.: 34 AF XY: 0.00240 AC XY: 1748 AN XY: 727144

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.0519

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0288

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00591 AC: 901 AN: 152342 Hom.: 33 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74490

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.0449

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00830

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs916657; hg19: chr17-26694890;