rs2227729

Variant names:

• chr17-28367275-A-G
• rs2227729
• ENST00000555059.2:c.329+176T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000555059.2(ENSG00000273171):​c.329+176T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 818,488 control chromosomes in the GnomAD database, including 4,727 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1289 hom., cov: 32)
  • Exomes 𝑓: 0.092 (3438 hom.)
• Consequence: ENSG00000273171 ENST00000555059.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.352
• Publications: 7 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VTN	NM_000638.4	c.*94T>C		downstream_gene_variant		ENST00000226218.9	NP_000629.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000273171	ENST00000555059.2	c.329+176T>C		intron_variant	Intron 2 of 3	4		ENSP00000452347.3
SARM1	ENST00000379061.8	n.170+2110A>G		intron_variant	Intron 2 of 10	2
ENSG00000258924	ENST00000591482.1	n.555+6428A>G		intron_variant	Intron 5 of 5	2
VTN	ENST00000226218.9	c.*94T>C		downstream_gene_variant		1	NM_000638.4	ENSP00000226218.4

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17892 AN: 151984 Hom.: 1275 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0959

Gnomad ASJ AF: 0.0787

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.0921 AC: 61388 AN: 666386 Hom.: 3438 Cov.: 9 AF XY: 0.0937 AC XY: 32028 AN XY: 341760

African (AFR) AF: 0.179 AC: 2861 AN: 15966

American (AMR) AF: 0.0813 AC: 1382 AN: 16998

Ashkenazi Jewish (ASJ) AF: 0.0739 AC: 1140 AN: 15436

East Asian (EAS) AF: 0.178 AC: 5466 AN: 30722

South Asian (SAS) AF: 0.151 AC: 7125 AN: 47086

European-Finnish (FIN) AF: 0.104 AC: 3712 AN: 35526

Middle Eastern (MID) AF: 0.0869 AC: 225 AN: 2588

European-Non Finnish (NFE) AF: 0.0770 AC: 36097 AN: 469028

Other (OTH) AF: 0.102 AC: 3380 AN: 33036

GnomAD4 genome AF: 0.118 AC: 17942 AN: 152102 Hom.: 1289 Cov.: 32 AF XY: 0.120 AC XY: 8918 AN XY: 74348

African (AFR) AF: 0.174 AC: 7220 AN: 41478

American (AMR) AF: 0.0958 AC: 1464 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 273 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1191 AN: 5160

South Asian (SAS) AF: 0.180 AC: 868 AN: 4822

European-Finnish (FIN) AF: 0.108 AC: 1139 AN: 10576

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0800 AC: 5442 AN: 67996

Other (OTH) AF: 0.121 AC: 255 AN: 2110

Alfa AF: 0.0896 Hom.: 781

Bravo AF: 0.118

Asia WGS AF: 0.233 AC: 806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.6
DANN	Benign	0.55
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227729; hg19: chr17-26694296;