NM_000638.4:c.1199C>T

Variant names:

• chr17-28367840-G-A
• rs704
• NM_000638.4:c.1199C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.51 (20437 hom., cov: 33)
  • Exomes 𝑓: 0.49 (175631 hom.)
• Consequence: VTN NM_000638.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.85
• Publications: 89 publications found

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]

ENSG00000273171 (HGNC:):

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

Our verdict: Benign. The variant received -13 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 VariationId is 3059155.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000638.4. 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
	VTN	NM_000638.4	MANE Select	c.1199C>T	p.Thr400Met	missense	Exon 7 of 8	NP_000629.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VTN	ENST00000226218.9	TSL:1 MANE Select	c.1199C>T	p.Thr400Met	missense	Exon 7 of 8	ENSP00000226218.4
	ENSG00000273171	ENST00000555059.2	TSL:4	c.173C>T	p.Thr58Met	missense	Exon 1 of 4	ENSP00000452347.3
	VTN	ENST00000886529.1		c.1199C>T	p.Thr400Met	missense	Exon 8 of 9	ENSP00000556588.1

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

GnomAD2 exomes AF: 0.509 AC: 126472 AN: 248412 AF XY: 0.503

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 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

African (AFR) AF: 0.568 AC: 19000 AN: 33478

American (AMR) AF: 0.570 AC: 25468 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12437 AN: 26134

East Asian (EAS) AF: 0.747 AC: 29667 AN: 39698

South Asian (SAS) AF: 0.476 AC: 41023 AN: 86256

European-Finnish (FIN) AF: 0.416 AC: 22196 AN: 53326

Middle Eastern (MID) AF: 0.479 AC: 2763 AN: 5768

European-Non Finnish (NFE) AF: 0.475 AC: 528714 AN: 1111938

Other (OTH) AF: 0.500 AC: 30171 AN: 60392

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

African (AFR) AF: 0.571 AC: 23691 AN: 41506

American (AMR) AF: 0.556 AC: 8503 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1625 AN: 3470

East Asian (EAS) AF: 0.723 AC: 3735 AN: 5164

South Asian (SAS) AF: 0.470 AC: 2267 AN: 4828

European-Finnish (FIN) AF: 0.406 AC: 4296 AN: 10592

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32529 AN: 67978

Other (OTH) AF: 0.520 AC: 1100 AN: 2114

Alfa AF: 0.493 Hom.: 54909

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	VTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000044	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.24
Sift	Benign	0.22	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.053
MPC		0.22
ClinPred		0.023	T
GERP RS		-8.9
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.29
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs704; hg19: chr17-26694861; COSMIC: COSV52647729; COSMIC: COSV52647729;